B RA I N RE SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9

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Review

Understanding wiring and volume transmission
Luigi F. Agnati a,⁎, Diego Guidolin b , Michele Guescini c , Susanna Genedani a , Kjell Fuxe d
a

IRCCS San Camillo Venezia, Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via Campi 287,
Modena 41100, Italy
b
Department of Human Anatomy and Physiology, University of Padova, Via Gabelli 65, Padova 35122, Italy
c
Department of Biomolecular Sciences, University of Urbino „Carlo B‛‛, Via A. Saffi 2, Urbino 61029, Italy
d
Department of Neuroscience, Division of Cellular and Molecular Neurochemistry, Karolinska Institutet, Retzius väg 8,
Stockholm 17177, Sweden

A R T I C LE I N FO

AB S T R A C T

Article history:

The proposal on the existence of two main modes of intercellular communication in the

Accepted 17 March 2010

central nervous system (CNS) was introduced in 1986 and called wiring transmission (WT)

Available online 27 March 2010

and volume transmission (VT). The major criterion for this classification was the different
characteristics of the communication channel with physical boundaries well delimited in

Keywords:

the case of WT (axons and their synapses; gap junctions) but not in the case of VT (the

Wiring transmission

extracellular fluid filled tortuous channels of the extracellular space and the cerebrospinal

Volume transmission

fluid filled ventricular space and sub-arachnoidal space). The basic dichotomic classification

Tunnelling nanotube

of intercellular communication in the brain is still considered valid, but recent evidence on

Roamer type of VT

the existence of unsuspected specialized structures for intercellular communication, such

Microvescicle

as microvesicles (exosomes and shedding vesicles) and tunnelling nanotubes, calls for a

Communication network

refinement of the original classification model. The proposed updating is based on criteria

Central nervous system

which are deduced not only from these new findings but also from concepts offered by
informatics to classify the communication networks in the CNS. These criteria allowed the
identification also of new sub-classes of WT and VT, namely the “tunnelling nanotube type
of WT” and the “Roamer type of VT.” In this novel type of VT microvesicles are safe vesicular
carriers for targeted intercellular communication of proteins, mtDNA and RNA in the CNS
flowing in the extracellular fluid along energy gradients to reach target cells. In the
tunnelling nanotubes proteins, mtDNA and RNA can migrate as well as entire organelles
such as mitochondria. Although the existence and the role of these new types of
intercellular communication in the CNS are still a matter of investigation and remain to
be fully demonstrated, the potential importance of these novel types of WT and VT for brain
function in health and disease is discussed.
© 2010 Elsevier B.V. All rights reserved.

⁎ Corresponding author. IRCCS San Camillo via Alberoni 70, Lido VE, Italy.
E-mail address: luigiagnati@tin.it (L.F. Agnati).
Abbreviations: AD, Alzheimer's disease; ASIC1a, acid-sensing ion channel 1a; CCNs, complex cellular networks; CL, cytoplasmic loop;
CNS, central nervous system; CSF, cerebrospinal fluid; Cxs, connexins; ECF, extracellular fluid; ECM, extracellular matrix; ECS,
extracellular space; GJ, gap junction; GMN, global molecular network; ILVs, intra-lumenal vesicles; MVB, multivesicular bodies; TM,
transmembrane domain; TNTs, tunnelling nanotubes; UCP, uncoupling protein; VT, volume transmission; WT, wiring transmission
0165-0173/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.brainresrev.2010.03.003

138

B RA I N R E SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9

Contents
1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1. Wiring transmission and volume transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.
Wiring transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Classical chemical synaptic transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Gap junctions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3. Mixed synapses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.
Volume transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Ephaptic transmission or electrical VT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Perisynaptic VT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3. Classical volume transmission beyond the perisynaptic region . . . . . . . . . . . . . . . . . . .
3.4. Possible interactions between transmitter spill-over and ephaptic effects at chemical synapses .
4.
Putative novel types of wiring and volume transmission . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Tunnelling nanotubes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Roamer type of VT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.
On the role of the extracellular space in intercellular communication . . . . . . . . . . . . . . . . . . .
6.
Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.

Introduction

In 1986 we published our original proposal on the existence
of two main modes of intercellular communication in the
CNS: the wiring transmission (WT) and the volume transmission (VT) (Agnati et al., 1986), which was aimed to
complement the Cajal's and Sherrington's view of the central
nervous system (CNS) as a computational apparatus basically formed by neurons interacting via specialized sites of
“contiguity,” namely the synaptic contacts (Cajal, 1906;
Sherrington, 1906) (Fig. 1). Our proposal was influenced by
previous important contributions on communication in the
CNS (Golgi, 1914; Guillemin, 1978; Nicholson, 1979; Schmitt,
1984; Descarries et al., 1991; Nieuwenhuys, 2000; Bach-Y-Rita,
2005) and based on a number of observations, especially on
the central monoamine neurons (for reviews: Fuxe and
Agnati, 1991a,b; Agnati and Fuxe, 2000). The concept of VT
introduced the extracellular space and the ventricular
system as important channels for chemical transmission in
the CNS complementary to WT with diffusion and flow of
transmitters, ions, trophic factors, ... in the extracellular fluid
(ECF) and cerebrospinal fluid (CSF). Furthermore, our proposal in 1986 considered that the VT signals could interconnect not only neurons in neuronal networks but rather cells
of any type (neurons, glia, microglia, ependymal cells,
macrophages,…) in what we have called the “complex
cellular networks” (CCNs) of the brain (Agnati and Fuxe,
2000). Thus, these signals migrating in the ECF of the CNS
could affect multiple targets in the CCNs.
In some instances they could even lead to a new output
from the same CCN as surmised within the concept of
“polymorphic networks” (Getting and Denkin, 1985) (see
Fig. 2 for an example of a VT modulation of a “polymorphic
neuronal network”). The existence of VT has also made it
possible to suggest different informational models for memory processes (Agnati and Fuxe, 2000; Guidolin et al., 2007) and
its relevance for neuropsychopharmacology (Zoli et al., 1999)
has been underlined.

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It is our opinion that the basic dichotomic classification of
intercellular communication in the brain proposed more
than two decades ago is still valid. However, we are fully
aware that evidence on the existence of new specialized
structures for intercellular communication, such as microvesicles (for a review, see Cocucci et al., 2009) and tunnelling
nanotubes (Rustom et al., 2004; Baluška et al., 2006; Goncharova and Tarakanov, 2008) (Fig. 3), calls for an updating of our
original conceptual model. This also includes the introduction by our concept that communication via both WT and VT
belongs to the fundamental features of all neurons, the ratio
of which can vary from one neuron system to the other and
with the structural and functional state of each neuron
system.
The criteria which can be applied to characterize WT and
VT and their sub-classes will be deduced not only from
structural and neurochemical findings, but also from concepts
and from the lexicon offered by informatics (Hopcroft and
Ullman, 1979). Our presentation will follow a historical frame
moving from the well established modes toward novel modes
of cell–cell communications. Thus, after a condensed summary of the main features of the “classical” modes of WT and
VT (Agnati and Fuxe, 2000) tunnelling nanotubes and microvesicles will be discussed as novel types of WT and VT,
respectively.
Furthermore, recent experimental findings of our group on
these new types of WT and VT will be presented and, finally,
their potential relevance for the physiology and pathology of
the CNS will be discussed.

1.1.

Wiring transmission and volume transmission

Taking advantage of some concepts and the lexicon offered by
informatics (Hopcroft and Ullman, 1979; Le Boudec and
Thiran, 2001), it becomes possible to classify the intercellular
communication in the CNS according to a series of criteria
based on the characteristics of the communication channel, of
the transmitted signal and of the formed network. They are

2007) to a more formal definition is also outlined. Let us now briefly examine them.e.” On the contrary. (2007c). On the contrary. The classification (in particular when VT based intercellular communication pathways are concerned). which are well delimited for WT but not for VT.e. which explains experimental evidence that could not be explained by the old paradigm. together with the properties they exhibit in terms of the criteria to classify modes of communication in cellular networks of the CNS (Table 1). by enzymes) in the extracellular space (ECS). As indicated in the figure. as occurring. a “reserved signal”) if only cells endowed with a specific recognition/decoding apparatus (as. • Signal safety: As far as the safety is concerned. However. could be further detailed by taking into account the other signal features illustrated in Table 1 (see also legend to Table 2): • Signal privacy: It is proposed that we are dealing with a signal characterized by high privacy (i.” The scheme in the figure illustrates the “classical paradigm” of inter-neuronal communication in the brain on which most of the approaches to Neurophysiology and Neuropathology have been founded. a “broadcasted signal”) when any cell reached by the signal can have access to it. The different subclasses of WT are indicated in Table 2. specific receptors) can have access to it. Thus. we are dealing with a “safe signal” if it is not altered during its conduction from the source to the target cell and with an “unsafe signal” if it can be altered during its pathway. 2. this conceptual model was proposed by Cajal and Sherrington at the beginning of the last Century (Sherrington. 1 – According to Kuhn's epistemology a “paradigm” allows to evaluate the relevance of facts in a given science (Kuhn. the structure of a communication network is “static” when the pattern of connections is almost stable in time... a unitary scheme could be devised for a more detailed characterization of WT and VT and of their subtypes.. see Agnati et al. however. 1906). any paradigm has a “physiological life span. they provide a “dynamic network. based on these concepts. In this respect it has to be observed that the one and main criterion which allows differentiating WT from VT are the characteristics of the communication channel and more precisely the physical boundaries of the channel. for instance.B RA I N RE SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9 139 Fig. for instance.” since it is sooner or later replaced by a new paradigm.g. illustrated in Table 1. • Connectivity: If the connections between cells can be rapidly formed or removed. . we are dealing with a low privacy signal (i. For further details. 1962). Thus. to some VT signals that can be broken down or modified (e. it occurs what Kuhn has called “an epistemological paradigm shift. where a possible approach (Ramanathan et al.. Wiring transmission The specific feature of this mode of intercellular communication is the existence of a virtual wire connecting the cell source of the signal (message) with the cell target of the signal.

2007) and with the “safety” of the message. 2003. a truly continuous wire connecting the source of the message with the target of the message and therefore all the above mentioned forms of WT share a high level of signal safety. Panel B: Output 2. Among them. Since TNTs represent a quite novel finding.1). Obviously. 2007.140 B RA I N R E SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9 Fig. only the synaptic transmission is also characterized by a high level of signal privacy based on specific receptor systems to decode the transmitted signal (Table 2). at least transiently. the same conceptual scheme can be applied to a Complex Cellular Network. is represented by the tunnelling nanotubes (TNTs) (Rustom et al. while the second one.. a small gap (the synaptic cleft less than 50 nm) in the channel is present between the site of release of the transmitter and the site where the receptors capable of detecting and transducing the signal are located. Classical chemical synaptic transmission It is beyond question that classic synaptic wiring. Actually. the clear-cut in vivo demonstration of which has not yet been provided. 2004).2. form gap junction (GJ) channels that provide a direct pathway for electrical and metabolic signaling between cells. which can give different outputs according to the VT signals impinging on it. is the most important example of WT and the primary mechanism through which neurons transmit information and control behavior. which depends on the transmission of action potentials. Moreover. is composed of two hemi-channels (connexons). 2. Yeager and Harris. Gap junctions Connexins (Cxs). as shown in this schematic drawing VT signals via modulatory actions on the synaptic contacts of the neuronal network can give rise to three types of outputs (Panel A: Output 1. This WT will be further discussed in relation to perisynaptic VT transmission. two more subclasses of WT could play some role in the CNS. as mentioned before. especially astrocytes (LeBeau et al. An example of a polymorphic network is illustrated for a neuronal network where the VT signals by up-regulating or down-regulating synaptic contacts can change the integrative action of the network. however.. It represents the prototype of the WT since it is characterized by a virtually continuous wire connecting the source of the message with its targets. 2. a large family of homologous membrane proteins in vertebrates. 2007). The WT mode of intercellular communication is characterized by a channel representing. which has an inner pore diameter of 10–12 Angs. they will be described in more detail than the other types of WT (see Section 4. 2 – Changes in the mix of VT and WT can also give rise to polymorphic networks that is to a neural network.. the signal can be classified as “reserved” since specific receptors are needed to decode the message (Table 2). The first one is represented by the well characterized gap junctions. However. The most important and well known is certainly the synaptic transmission. Each GJ channel. in the “classical synaptic transmission” it is assumed that this gap does not interfere with the continuity of the channel (Savtchenko and Rusakov. which in turn are composed of . Hervé et al. Thus. However.1. Panel C: Output 3).

Volterra and Meldolesi. Gap junctions are also found between activated microglia. 2008). The opening probability of the hemi-channels increases markedly by reducing the concentrations of divalent cations. 2004). Exosomes are microvesicles with a diameter of 40–100 nm that originate in multivesicular-bodies of the endosomal system. exosomes and shedding vesicles. Each of the six Cx subunits forming a connexon has four alpha helical transmembrane domains (TM1 to TM4).B RA I N RE SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9 141 Fig.. usually different astro- cytes are coupled through gap junctions to form large intercellular networks (Theis et al.. 2005). and in a few somewhat controversial instances between astrocytes and neurons (Nagya et al. which are organized clusters of macromolecules involved in the recognition/decoding of chemical signals. The function of these gap junctions is to minimize the differences not only between individual processes of the same astrocyte but also between astrocytes by mediating the sharing of substrates such as glucose. Both types of Microvesicles play a role as safe vesicular carriers for targeted intercellular communication via VT allowing the transfer of “packets of signals” to target cells. the communication network generated by gap junctions in astrocytes is also of significant support to the main processing network formed by the synaptic wiring among neurons. 2004).and Ctermini. Cocucci et al. the question has been raised as to their possible different functional meaning. intracellular N. 2009 and Table 3) Microvesicles can be subdivided into two main classes. Actually. It is also illustrated that the exosomes can undergo endocytosis as they impinge on the target cell. since gap junction channels allow the coordination of intrinsic or elicited metabolic and/or electrical responses of cells in a heterogeneous population. whose extracellular accumulation can be detrimental for the proper neuronal functions.g. two extracellular loops. Other endosomes are shown to be inserted into the plasma membrane and into organelles. Exosomes via exocytosis are released both constitutively and in a regulated manner. Channel conductance and . Gap junctions are evenly distributed along the astrocytic processes. 3 – Schematic representation of the main features of tunnelling nanotubes and microvesicles. It is illustrated how they may be formed by budding from lipid rafts and also how they may impinge on the plasma membrane of target cells and may transfer lipid rafts with associated signalosomes. and is accompanied by the release of both ATP and glutamate. including the receptor mosaics. However. The control of opening probability is important. Shedding vesicles are formed from lipid raft domains of the plasma membrane. six Cx subunits. they play a role in dissipating extracellular K+ or glutamate.. often interconnecting adjacent astrocytic processes derived from the same cell. Furthermore.. channels vary in permeability selectivity from being non-selective. see Table 4 and text. and a cytoplasmic loop (CL). or being preferentially selective for cations or anions (Oviedo-Orta and Evans. Thus. It should be mentioned that lipid rafts often contain signalosomes.. Connexons can be coupled with a hemichannel of an adjacent cell to form a gap junction. notably Ca2+. For further details. e. 2005. between many types of neurons. between astrocytes and oligodendrocytes (Orthmann-Murphy et al. Since at least 20 distinct Cx isoforms have been cloned. According to several authors (see.

González et al. Thus.b. It has to be pointed out. 1980. Geffen et al.. 2004. 1996).. The half-life of several rodent connexins has been found to be between 2 and 5 h (for reviews: Saez et al. 2. 1 ≤ i ≤ N} the set of vertices (nodes) E = { (u. Bloom and Segal. Thus.E) where G is a graph. hence “mixed synapses” are possible. Furthermore. 1969. that in the mammalian CNS. imparting fundamental alterations to their properties.v∈V(t) and communicating at time t} Signal needing a specific “decoder” to be decrypted Neurotransmitters and. In the 1970s and 1980s.. De Wied and Jolles. it should also be mentioned that some gap junctions (nonrectifying gap junctions) allow the bidirectional passage of the electrical signal (Nagya et al.. however. i. 3. .3. Mixed synapses Gap junctions can also be observed in chemical synapses. 2009). 1977. no end-to-end path is present between two communicating nodes. i... 2008). 1982. 1976) and peptidergic neurons (Fuxe et al. such as IP3 and Ca2+ and other low molecular weight substances such as small peptides (less than 1000 Da (Oviedo-Orta and Evans.v): u. E(t)) Where: E(t) = {(u.. Volume transmission Interneuronal wiring communication is certainly a basic feature of the CNS and has been the main foundation of neuroscience as we know it. 2007a). 1986). Flores et al. It has been surmised that in the mixed synapse direct physical interactions between receptors and connexins could play an important role (see Fuxe et al..e. a 2-ple composed by V = { vi. This type of channel characterizes VT permeability are under a control carried out by changes in the gating mechanisms and by changes in the Cx turnover (Goldberg et al. since the transient interconnec- tions of the two cytoplasms via the gap junctions allow the protected intercellular transfer of second messengers. signals using specific receptor systems are of this type “Public” signal.. 2002). Burbach. more generally. Network feature Connectivity Types Static Dynamic Signal privacy Reserved Broadcast Signal safety Channel (Main criterion to distinguish volume transmission from wiring transmission) Unsafe Safe Private Diffuse Description The network structure does not change with time. and also of siRNAs (Valiunas et al.e.. 2005). It should be considered that also some additional features are added to the exchange of signals from the pre-synaptic to the post-synaptic side thanks to the presence of a gap junction. however. 2003a. Bloomfield and Völgyi. 2004.. but there is a temporally ordered sequence of events that connects the two nodes... This type of channel characterizes WT The whole available space between the network nodes is potentially used to exchange signals. interpreted by all the involved elements Physical quantities or membrane permeable molecules are of this type The signal can be altered during its travel from the source node to the destination node The signal comes to the destination node without alteration Physically delimited pathway between two nodes of the network. Contreras et al. 1996. 1982) and led to the definition of VT (Agnati et al. 2007).. From a formal point of view it can be defined as: G = (V. the physiological roles and distributions of mixed synapses are still to be clearly established (Rash et al.142 B RA I N R E SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9 Table 1 – Possible informatics criteria to classify communication networks of CNS.. The presence of both types of synaptic communications allows a more subtle and complex neuronal computation than might occur with only one type of synaptic contact. the functional assumption of a diffuse mode of intercellular communication affecting and modulating the activity of entire brain regions was gaining support from studies on monoaminergic (see Ungerstedt et al.v): u. mixed synapses provide the structural and functional components required for both chemical and electrical transmission within a single synaptic contact on an individual postsynaptic element (Rash et al..v∈ V} the set of edges (connections) The network has a time-varying structure At a particular instant of time t it can be described as: G(t) = (V(t). 2004)). which may have a significant modulatory role on the neural networks.

hence signals can potentially migrate in any direction . CO). involved via its modulatory action on pH in the tonic control of neuronal excitability and in protein 3D-conformations (see Petsko and Ringe. 2005). or endowed with such specializations. 2008). 2008). 2008 for a review on ‘silent synapses’) whenever needed. However.1) Perisynaptic transmission (Section 2. 1985. as well as dynamic networks in which a number of connections are ex novo established (see.Physical signals (as. evidence has been provided that carbonic anhydrase-II is localized in the CNS to wide spread systems of oligodendrocytes and restricted astroglia populations. neuromodulators.. Network Synaptic transmission (Section 1... the neural circuitry responsible for seasonal breading in several species.g. As detailed in Table 3. functions as a proton receptor. give rise to protons controlling the excitability of surrounding neuropil (see Sun and Alkon. where the available supporting evidence is reported. CO2. Adams et al. Hensch.1) Roamer type of VT (Section 23. They include networks that once established exhibit an almost stable (static) configuration (as.2) Signal privacy Signal safety Channel Connectivity Reserved Broadcast Broadcast Reserved Reserved (common) or broadcast (rare) Broadcast Reserved or Broadcast Safe Safe Safe Unsafe Unsafe Private (WT) Private (WT) Diffuse (VT) Diffuse (VT) Diffuse (VT) Static and/or dynamic a Dynamic Dynamic b Dynamic Dynamic Safe Safe Private (WT) Diffuse (VT) Dynamic Dynamic Definitions of the terms: - Reserved: a specialized receptor apparatus is needed to decode the message Broadcast: no specialized receptor apparatus is needed to decode the message Private: the channel transmit signals along a conductor with clear cut physical boundaries Diffuse: the channel transmits signals along a conductor without clear cut physical boundaries. oligodendroglial and ependymal cells.. a Synaptic transmission is endowed with a potential high plasticity. for instance. which is localized in dendritic spines.Static: the connection between the source and the target is maintained for relatively long periods of time (sometimes for a life-long period) .Classical and non-classical intercellular chemical mediators: neurotransmitters. As a matter of fact. gases (NO. Thus. Thus. which are the postsynaptic site of most . hence from dendrites. 2000) between cells and filled with extracellular fluid and extracellular matrix.143 B RA I N RE SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9 Table 2 – Summary of the different types of wiring transmission and volume transmission forming the communication networks of the brain ( see Table 1).. Ca2+). Moreover.. if they are inactivated by enzymes or cleared over the brain capillaries (Jansson.1) Gap junctions (Section 1. rather than broadcasted.. 1995a. involving both fiber bundles and neuropil (Agnati et al. 2006) or re-activated (see Kerchner and Nicoll. ions (e. . because it affects the density of spines. since while the first ones can diffuse also across membranes (i. via carbonic anhydrase-II.2) Classical volume transmission (beyond the perisynaptic region) (Section 2.3) TNT (Section 3. which can affect the diffusion pathways of ion currents (see also the text). CO2 may represent an important. we should mention two typical examples of broadcasted VT signals. VT can employ the same set of signals as WT. It is also important to note that CO2 can also operate as a “reserved” signal.e. were suggested to be linked to VT (see Getting and Denkin. 2000) or taken up into cells via transporters (Rice and Cragg. since the acid-sensing ion channel 1a (ASIC1a).2) Ephaptic transmission (Section 2. Chen and Nicholson. they have a large space of diffusion) the latter ones are practically confined to the ECS. 2004). 1994.b. and unsafe. highly diffusible. As stated in Table 2 most of the VT signals are reserved.Safe: the signal is not altered during its conduction from the source to the target . hence it could give rise to neural networks characterized by different types of connectivity. “broadcasted" signal in classical VT in the brain. for instance. 2003). 1995d). the field potentials and the CO2. it is important to distinguish lipophilic from hydrophilic VT signals. field potentials). Let us briefly examine some of these VT signals and their main features. Fuxe et al. Such a channel can modulate the local circuitry of the neuronal network. namely transmitters and ions. however.. 2002). which can be also related to each other via their effects on the membrane potential of neurons and astrocytes. for instance in the primary visual cortex. growth factors. b Ephaptic transmission is highly dependent on the volume fraction of the ECS and the composition of the ECM. 2005a. microglial. It has also been suggested that CO2 formed in activated axons may. it is possible to list the VT signals as follows: .Dynamic: the connection between the source and the target can be rapidly formed and/or removed. Agnati et al. VT signals can be released from any type of brain cells. VT is characterized by the absence of any wire-like channel connecting the source of the signal with its own targets and this feature usually leads to reduced safety since the VT signal migrates in the ECF (Tables 1 and 2). Other types of signals. Signals migrate in the extracellular space and may be stopped if they reach a blind alley (a cul-de-sac) (Hrabetová et al. and from astroglial. soma and axon terminals (varicosities) entirely lacking synaptic membrane specializations (asynaptic) (Descarries et al. 2010). This communication mode uses several often spatially divergent tortuous channels made by the clefts (about 20 nm in diameters.

. (1998) Lendvai & Vizi (2008) Descarries & Mechawar (2000) Oláh et al. it has also been proposed that classical VT communication is involved in intercellular RNA transfer.. (2004) Clark & Cull-Candy (2002) Floresco et al. Faster form of non-synaptic transmission operating at short distances GABA released from neurogliaform cells acts as a volume transmitter Alterations in carbonic anhydrase activity in hippocampal CA1 neurons provide a mechanism for switching between operational states at GABA-releasing synapses. Thus.. which are major neurotransmitters (Barañano et al. (2009) Sun & Alkon (2002) rhythms and regulating its DNA binding activity (Boehning and Snyder. thereby gating signal transfer through the hippocampal network excitatory synapses.. without changing transmitter release Released β-endorphin after stimulation of arcuate nucleus reaches other brain areas and affect brain function in a global manner Inhibitory modulation of 5.HT1A receptor affinity and efficacy. 1988. which is not a proper receptor but gives specificity to their action. Their main molecular target is an intracellular enzyme (the heme moiety of soluble guanylyl cyclase). (2003) Mundorf et al. (2004) Ciranna (2006) Bunin and Wightman (1998) Jansson et al. namely the gases NO and CO. 2002) Descarries & Mechawar (2000) Kullmann et al. In this brief list of VT signals. 2007a) and this is also true for large peptides such as Abeta (Agnati et al.. (1998. Signaling molecule 5-HT Glutamate DA Animal Rat Rat Rat Mouse Brain regions Hippocampus Frontal cortex Cerebellum Dorsal raphe nucleus or Substantia nigra pars reticulata Spinal cord: dorsal and ventral horn Hippocampal slices Cerebellar slices Ventral pallidum Ventral subiculum Pedunculopontine nucleus Findings Existence of extrasynaptic receptors and transporters for 5-HT Diffusion of 5-HT for a few microns 5-HT receptors on neurons not receiving a direct 5-HT innervation 5-HT fibers often lack typical synaptic contacts Electrochemical studies show that 5-HT can enter the extracellular space 5-HT diffusion in the order of 8 μm Glutamate spill-over Astroglia processes and neuronal glutamate transporters modulate spill-over Astroglial release of glutamate Synaptically released glutamate can exert long-range actions in the cortical microcircuitry NMDARs involved in the response to extrasynaptically released glutamate Extrasynaptic tonic DA release Diffusion is the most important determinant of DA time-course VT model of DA varicosity NE Mouse Brain slices Prefrontal cortex Brain slices Hippocampus Neocortex Brainstem slices containing the superior olivary complex Mid brain Cerebral cortex Ca2+ Rat NO Mouse β-endorphin Rat Galanin Rat Ach Rat GABA Rat Raphe region Amygdale Parietal cortex Hippocampus Somatosensory cortex CO2 Rat Hippocampus Mismatch between D4 IR . 2001) should be mentioned. It has been shown that also high-molecular weight proteins (e. (2001) Yano et al. participating in circadian References Bunin and Wightman (1999) Ridet and Privat (2000) Doly et al. 2000. decreasing ASIC1a reduces the number of spines.. (2004) Diamond (2001) Scimemi et al. (2001) Rice & Cragg (2008) Rivera et al. (1998) Fuxe et al. migrating in the extracellular fluid of the brain and signaling to target cells (Fuxe et al. 2001. 2002). (2003) Goto et al. (2003) Szapiro & Barbour (2007) Piet et al. (2007) Floresco (2007) Cragg et al. Bjelke et al.. (2006) Rivera et al. (2004) Steinert et al. 2007b. In addition CO formed from heme oxygenase 2 specifically binds to the transcription factor NPAS2. Furthermore. (2008) Fuxe et al.g.144 B RA I N R E SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9 Table 3 – Chemical mediators involved in VT. Fuxe et al. whereas over-expressing ASIC1a has the opposite effect (Zha et al. since RNAs may be secreted into extracellular spaces despite their . TH IR and β-hydroxylase IR NE remains in the extracellular space for a time sufficient to travel ∼ 100 µm Presence of calcium sensing G protein-coupled receptors in the brain Suppresses postsynaptic Kv3 potassium currents Inhibits postsynaptic glutamate receptors. two highly lipophilic “reserved” signals. 2006). (1996) Del Arco et al. Jansson.. (2008) MacMillan et al. 1977. Leo et al. prolactin and interleukin1-beta) can participate in classical VT. 2007).

the shrinkage of the volume fraction via cell swelling may increase the brain 145 tissue electrical resistance and reduce ephaptic transmission as well as VT in general (Syková et al. 2004). 3. when glutamate escapes from a synaptic cleft or is released by astrocytes. the fate of the escaping transmitter molecules is determined by the activity of the transmitter transporters and/or the inactivating enzymes. 2004.and post-synaptic membrane. during lactation or dehydration. 2000. which may be a clue to indicate that the secreted RNAs comprise a VT form of cell–cell communication. the glial envelope of the synapse and its membrane specializations are the hallmark of synaptic transmission favoring a point to point communication.1. 2010. Thus. who proposed neurotransmitter spill-over as one mechanism for intersynaptic crosstalk (Gonon et al. indeed. Thus. 2000).B RA I N RE SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9 susceptibility to degradation by extracellular RNAses (Alvarez et al. Kullmann. the astroglia and even adjacent synapses. extracellular RNAses appear to have a regulatory role in cell physiology... Golgi based his bold statement on Volta's studies on the second class of conductors. 2001. Based on the criteria reported in Table 1. 1993) also in the brain especially in the glial networks. forming perineuronal nets (Celio et al. 2010). Sykova. a process regulated also by the affinity of the glial and neuronal transporters of glutamate and GABA and also leading to astroglial release of glutamate (Olàh et al...e. Syková et al.. 2008). i. However... 2006..2. 1999). Smalheiser. This important field of investigation was initiated in the midnineties mainly by Gonon and Kullmann.. which are electrolytic solutions. 2000. A special case is represented by the calcium ion fluxes since there does exist a calcium sensing G protein-coupled receptor (Brown et al.. 1996. the so-called volume conductors. Asztely et al. synaptic spill-over favors their crosstalk. 2007).. However. It has been observed that ephaptic interactions between a neuron and axons or dendrites passing by its cell body can be. Golgi postulated it by stating that the material contact between neurons is not a necessary condition for their communication by electrical signals. Cabello et al. 2007. Bicker and Schratt. 2007a for a review).. In addition. 2007. ephaptic transmission involves electrical signaling due to the flow of ions between neurons and/or axons through a “volume conductor.” the ECF. mainly excitatory or inhibitory effects could be predicted theoretically and demonstrated in experiments (Krnjevic. 2000). Alle and Geiger. 1998. In agreement with Golgi's proposal. The ionic currents of ephaptic transmission can generally affect all the cells they reach independent of receptors and therefore act as broadcasted signals. The safety of ephaptic transmission is high since the volume fraction of the extracellular space allows substantial ion fluxes to take place (Nicholson. Glutamate released during synaptic events could escape the synaptic cleft and reach NMDA receptors at neighboring synapses (Kullmann et al. 1997). when the pre-synaptic terminals of two neighboring synapses are near to one another and a paucity of glial membranes is interposed. glial sheaths around the synapse and the extracellular matrix (ECM). such as body fluids. during repetitive stimulation.. where it can potentiate neurohormonal release (Oliet et al.. 1999). As a matter of fact. 2009) and finally leading to “synaptic spillover” to other synapses (Piet et al. even in the classical synapse where signaling occurs through the “private” synaptic cleft. Ephaptic transmission or electrical VT This was the first type of VT to be proposed to exist in the CNS (Golgi. 2010). 3. Eyman et al. 1998) act as diffusion barriers. Thus. with the synaptic transmitter reaching the perisynaptic domains of the pre. 2000). the insulation of the synapses is often insufficient to prevent perisynaptic VT (Oliet et al. 1986). see Fuxe et al. 2007c. It has been suggested that this type of intercellular communication plays a role in long-term potentiation and depression. Ferré et al. in principle. it is accepted that via diffusion. Thus. It should be noted that even if the term ephaptic comes from the Greek word εϕαπτειν (ephaptein) which means “to bind... more significant than ephaptic interactions among axons in a fiber tract. the classical neurotransmitters glutamate or GABA can reach receptors at astroglia and at neighboring synapses affecting the efficacy of transmission (Reichenbach et al. 2008). 2007. while they are larger in amplitude and much more spatially confined near cell bodies (Holt and Koch. As indicated above. Syková and Vargová. different subclasses of VT could be differentiated. 2007. Calcium ion fluxes should. it reaches a relatively high concentration in narrow extracellular clefts and diffuses from the place of release if it is able to overcome not only the physical barriers to diffusion (Nicholson and Sykova. Extracellular action potentials outside axons are small in amplitude and spatially spread out. 1891) and the main one to inspire us in proposing the VT mode as a significant communication mode in the brain in view of its self-evident existence deriving from physical concepts already well established by Volta two centuries ago (Trasatti.. Thus. 1). 2010) with the diffusion of mediators from the synaptic cleft reaching perisynaptic regions and astroglia rich in receptors (Deitmer and Rose.” ephaptic interactions occur between neurons or parts of neurons in close contiguity but not in continuity with each other (Fig.. be considered also as a signal of the reserved type (Yano et al.. see Agnati et al. As a matter of fact. 2000. therefore. Witcher et al. They are summarized in Table 2 and discussed in the next sections. .. 2008) but also the buffering action of the uptake systems present in neurons and astrocytes (Rice and Cragg. what is the relative importance of this type of transmission? It seems that both synaptic transmission and perisynaptic VT belong to the fundamental properties of neurons and both participate in the integrative processes of the local circuits (Schmitt. Perisynaptic VT Perisynaptic VT is linked to synaptic transmission and likely takes place to a varying degree as a consequence of synaptic transmission due to incomplete diffusion barriers. Depending on the direction of the predominant current flow near the sites of spike initiation. 1984.. changes in excitability evoked by passive current flows between adjacent cells were described by Arvanitaki (1942) as opposed to synaptic transmissions at sites of specialized junctions and Kamermans and Fahrenfort (2004) provided evidence of ephaptic modulation within a chemical synapse. Nevertheless.

Fuxe et al. and the density of GABA transporters near the GABA release sources. 2006). which respond to membrane tension (Paoletti and Ascher. Thus. (d) temperature macrogradients (i. Piet et al. which flows through ventricles. where the intrinsic brain dynamics within the cranium is altered. 2001). since the VT signal is decoded by specific receptors. detected by metabotropic. Such a cyclic phenomenon has profound effects on the dynamics of cerebral blood and CSF flow and hence on the migration of signals in the extracellular space of the brain (see the “Tide Hypothesis” Agnati et al.. 3.. Possible interactions between transmitter spill-over and ephaptic effects at chemical synapses The amplitude of excitatory postsynaptic potentials and currents increases with membrane potential hyper-polarization. In contrast. Thus.146 B RA I N R E SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9 2001. 2007a. or in the indirect modulation of the dopaminergic system by excitatory inputs (Kiss et al. subarachnoidal spaces. 2008). This allows them to mediate persistent tonic current. Classical volume transmission beyond the perisynaptic region This type of VT is characterized by longer distances of VT migration (Agnati et al. 2007) and also on the NMDA channels.and post-synaptic level.. the homeostasis of the brain internal milieu).. It should be noted that this type of cell–cell communication is plastic..b.4. 2002..b.. (c) pressure gradients (vector mediated migration) (see the “tide hypothesis” Agnati et al. in some instances. also favor VT signal migration. 1991a.. 2005a).. Very recently this physical phenomenon has been carefully evaluated by means of MRI and computer-assisted image analysis (Linninger et al. Of particular importance is the role played by the CSF. 2007c. It is important to underline that while these studies give further support to the tide hypothesis (Agnati et al. 2001. Fuxe et al. 2001)).. 1986. VT occurs both at lower costs in terms of energy than the classical synaptic transmission (the prototype of WT). 1986. 1991. Rivera et al. 3. Fuxe and Agnati. Also GABA can operate as a perisynaptic transmitter in several brain regions and extra-synaptic GABAA receptors have been shown to have a higher affinity to GABA and slower kinetics of desensitization than the corresponding synaptic GABAA receptors (Kullmann et al. and a more widespread and diffuse signal to presynaptic and heterosynaptic structures. This is evident by the frequent existence of non-junctional varicosities (Descarries and Mechawar. It should also be considered that VT signals likely can diffuse into an unshielded synaptic cleft and if receptors capable of detecting these VT signals are present. the proximity of these receptors to the GABA release sources. The signals (released by any type of cells) involved in this type of VT are driven toward the target cells (any type of cells) by several energy gradients resulting not only in diffusion but also in flow of the VT signal in moving ECF (vector mediated migration). 2001) suggesting a major role in perisynaptic GABA VT. 2004). complex WT/VT integrative interactions can occur at both pre.. Ostrow and Sachs.. and with much lower space filling since VT does not need a dedicated channel but takes advantage of the ECS (Agnati et al. and the porous parenchyma in a pulsatile manner (Tawse. 1993.. On this basis a mathematical modeling has been developed which allows quantifying human intracranial dynamics. Pressure waves could also exert effects on the stretch sensitive ion channels present in some neurons and astrocytes (Puro. 2010) and is characterized by signals of the reserved type. Thus. D2-NMDA heteromers may exist in cortico-striatal glutamate synapses (Liu et al. 2005a. 2005a. It should be noted that pressure and temperature gradients besides enabling the extracellular fluid renewal (i. during neuronal activity. 2000.g. As demonstrated by Greitz (1993. Descarries et al. Instead the GABAB receptors are mainly located extra-synaptically (Charles et al. glutamate is allowed to diffuse relatively freely to receptors on and around pre-synaptic terminals (Barbour. The energy gradients for VT signal migration are: (a) concentration gradients of the VT signal (diffusion).g. 1996... 1996. the vascular system can induce a net motion of the solid brain which in turn induces the pulsatile cerebrospinal fluid flow which can enhance VT signal migration. 2004). 2007. 2010). This has been attributed to an increase in the driving force when .. 2005. 2002). It appears that the activation of extra-synaptic receptors at and around the postsynaptic target may be tightly regulated. 2006) which when reached by diffusing DA can lead to integration of WT and VT transmission through tuning of the NMDA mediated glutamate signaling in these heteromers via D2-NMDA receptor–receptor interactions (Fuxe et al. Fuxe et al. 2007c). 2007c). 2007a. 2000. they can also shed light on some symptoms present in pathologic conditions such as the hydrocephalus. 2005..e. Honorè. 2005a) on VT signal migration. The classical VT beyond the perisynaptic region usually exhibits a low signal safety (Table 2 and Agnati et al. pressure waves generated by the rhythmic cardiac activity pervade and deform the entire mass of the brain. Jansson et al. This can be the case for DA which mainly operates as a VT signal (Fuxe et al. 2005a. since the astrocytic isolation of synapses may change over either a short time-scale (e. 1994).. Sykova. 2006a.. It is clear that one and the same transmitter released by one and the same neuron can operate both as a synaptic and as a perisynaptic signal. (b) gradients of electrical potentials (for charged signals).. during lactation (Theodosis and Poulain.. 2001. Agnati and Fuxe. This appears to allow the same neurotransmitter to carry two types of information: a highly focused orthodromic signal that can be modulated by the action of neuronal and glial transporters... and a dominance of extra-synaptic receptors and transmitterreceptor mismatches in these neurons (Agnati et al. which is determined by several factors such as the density of extra-synaptic GABAA receptors.3. 2005). 2009). with the exception of CO2 (for more details see Section 3). 2006).. 2004) or over a long time-scale (e.. 2010). 1991a.. 2008). Haydon. kainate and possibly NMDA receptors (Rusakov and Lehreb. Fuxe et al. 2006a). Agnati and Fuxe. Hirrlinger et al.. between a brain active region and a brain inactive region (Yablonskiy et al.b) and is probably the major mode of communication in monoamine and peptide neurons in the CNS (Fuxe and Agnati. 2008).e.. 2000) and micro-gradients via uncoupling protein (UCP) (vector mediated migration) (Agnati et al.

4 – Intercellular migration of mitochondria via tunnelling nanotubes (TNTs). are given. their specific relevance for cell–cell communication. that the electrical field setup by AMPA receptor-mediated excitatory currents accelerates the clearance of negatively charged glutamate molecules from the synaptic cleft. 2004). respectively. 2010. Thus. University of Modena and Reggio Emilia). allowing a larger or lower sphere of influence for perisynaptic VT signals depending on the charge of the transmitter. This result is in agreement with the hypothesis of Byzov (Byzov and Maksimov.1. Tunnelling nanotubes Tunnelling nanotubes are structures involved in the intercellular communication. there are several findings demonstrating the existence of exosomes (more generally of micro-vesicles. that it is still a matter of investigation whether TNTs exist in vivo. in panels A and A’ the discriminated images of the WGA staining for astrocyte and glioblastoma cells. possibly. for instance. .. Cortical rat astrocyte or glioblastoma (U57MG) cell cultures were labeled by MitoTracker (MT) Green FM to visualize mitochondria and by wheat germ agglutinin (WGA) Alexa Fluor 594 conjugate (red. respectively. which has no Fig. 1998) on the existence of electrical (or ephaptic) linking in purely chemical synapses (Voronin et al. is still a matter of very intense investigations. especially in the brain. respectively. speeding up synaptic responses and.B RA I N RE SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9 the membrane potential deviates from the equilibrium potential of the respective ions. A discrimination procedure on the two panels was performed by means of a computer-assisted image analyzer (Zeiss Kontron KS400). This image has been kindly provided by Dr.. TNTs and exosomes may represent novel types of WT and VT. see also Agnati et al. are given. Chiara Carone (Department of Biomedical Sciences. It has been shown that in a subset of neocortical and hippocampal synapses postsynaptic hyperpolarization causes increased pre-synaptic release of the transmitter. Putative novel types of wiring and volume transmission As mentioned above. the electrostatic interactions between charged membranes and charged signals may have effects on their diffusion. Instead in panels B and B’ the discriminated images of the MT staining for astrocyte and glioblastoma cells. 147 4. A new aspect to be considered is the relationship between the electrical charge of the signals and the cell membrane polarization and hence between ephaptic effects at a chemical synapse and transmitter spill-over. Live cells were observed by confocal laser microscopy and the respective images of the two stainings for astrocyte and glioblastoma cells were acquired (upper and lower panels on the left).. increasing glutamate spill-over (Sylantyev et al. plasma membrane marker) to visualize TNTs. In fact. which have been recently discovered by means of in vitro studies (Rustom et al. However. On the other hand. 4.. 2008). in particular in the brain (see below). It has been shown. however. It has to be pointed out. see below) in vivo both in physiological and in pathological conditions. In a transient way they connect two cells forming a “private” direct channel. 1999). Intercellular transfer of mitochondria via TNTs was observed (see circle in panels B and B’).

2006. 2004. 2009).. PC12 cells and cells from human glioblastoma (see Rustom. 2006. Agnati et al. Main features Size Site of generation Type of generation Mechanism of generation Sorting Intracellular storage Mechanism of discharge Type of discharge Typical membrane proteins Typical lumenal proteins Typical lipids mtDNA transfer b mRNA transfer Possible physiological role Possible pathological role Exosomes Shedding vesicles 30–100 nm Late endosomes (a type of MVBs) Constitutive Budding Ceramide-dependent Yes Exocytosis of MVBs Constitutive and regulated CD9. Ambudkar et al. Onfelt et al. MVB. . 2006. proteins. regions of close contiguity between cell membranes. kidney cells. lipids and cytoplasmic components thanks to a direct cell–cell contact. more ordered and less fluid domains than the surrounding membrane. These transcellular channels could lead to the formation of syncytial cellular networks (Rustom et al.. TNFR1. and of transient fusions between the plasma membranes of neighboring cells (Niu et al. Goncharova and Tarakanov. In addition to transfer of organelles. 2005. 2010). 2005.. the in vivo experimental evidence of TNTs being limited to the MHC class II+ cells in the mouse cornea (Chinnery et al. GPI.. As mentioned above. 2009).. 2008). 2008). Belting and Wittrup.. In some instances also the transfer of cytoplasmic macromolecules up to 40 kDa between somatic cells could be demonstrated (Onfelt et al. GPI-anchored proteins. Agnati et al. 2004. Gerdes and Carvalho... they are transient structures having variable lifetimes ranging from less than 60 min (T cells) up to several hours (PC12 cells) (Gurke et al.. which allows spontaneous intercellular transfer of cellular components (ICT).. intercellular transfer of ‘signalosomes’ Stroke. future studies are required to better characterize the properties of ICT.. Furthermore. 2008). the role of membrane juxtapositions (Shepherd. integrins Caspase. for a comprehensive review).148 B RA I N R E SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9 gaps. provided this mode of communication is really used by neurons and/or by the other cell types in the CNS.. 2005. glucosylphosphatidylinositol tail. CD63 members of the tetraspanin family. 2008.. It may also be surmised that membrane receptors can move from the plasma membrane of one cell to the plasma membrane of another cell. Gousset et al. 2008a. Thus. 2009). In this respect. Studies carried out in co-cultures of different cell types containing distinct levels of proteins or markers for the plasma membrane or cytoplasm provided some support to this possibility.20-lysobisphosphatidic acid... TNTs have a diameter of 50–200 nm and a length up to several cell diameters. and whole organelles between cells (Rustom et al..e.. Sowinski et al. i. In this context. TNFR1.. 2004. resembling plasmodesmata of plant cells (Pontes et al. Rechavi et al. Agnati et al. a Cholesterol and saturated fatty acids can form lipid rafts. multivesicular bodies. Koyanagi et al.. Davis and Sowinski. tumor necrosis factor receptor 1. these mechanisms could represent an interesting and significant type of WT. CD63.. Mitochondria can also migrate unidirectionally along TNTs from one cell to neighboring cells either inside or along their surface (see Fig. Onfelt et al. 2010). 1994). 2006. Gurke et al. 2004.. Onfelt et al. it has to be pointed out that significant in vivo data are almost lacking. FGF2 Cholesterol and saturated fatty acids a Unknown Yes Epigenesis. Alix Cytokines LBPA. 2004. 2008. 2006. a phospholipid accumulated in the membrane of exosomes. mitochondrial DNA as well as RNA can migrate along TNTs from one cell to neighboring cells (Rustom et al. 2010). Watkins and Salter. 2008). Baluška et al. 2005).. ceramide Yes Yes Epigenesis.. 2008b.. 2.b.. indicating that a variety of trans-membrane proteins and lipids are transferred between multiple cell types (Koyanagi et al. coagulation. 2010). it has been shown that membrane proteins can be exchanged unidirectionally between cells either along the membrane of TNTs or during phases of their transient contacts (Rustom et al. Endosomerelated organelles like mitochondria and melanosomes are unidirectionally transferred via actin-mediated mechanisms at a speed of about 25 nm s−1 in PC12 cells (Gurke et al. b See text (Guescini et al. 2008. LSBPA.. they have been identified in a variety of cultured cell systems. 2008a. tumor progression Abbreviations: CD9. Vidulescu et al. as well as the cell types that in vivo can utilize this possible communication mode belonging to WT. including cells of the immune system. intercellular transfer of ‘packets of signals’ Alzheimer's progression 100–200 nm Plasma membrane (lipid rafts?) Regulated Budding Unknown No Budding from the plasma membranes Regulated and possibly constitutive Metalloproteinases. As far as animal cells are concerned. 2006. 2004. Tsg101.. Onfelt et al. 2008b). 2009.. Therefore. which through this mechanism can acquire for a transient period of time the capability to recognize and transduce signals otherwise not recognized. 2009). plasma membrane components such as lipid-anchored proteins can laterally transfer along TNT-like bridges into the plasma membrane of connected cells (Gurke et al. Table 4 – Sources of the Roamer type of volume transmission (modified from Cocucci et al.. Gurke et al. Thus.. 2008b). inflammation.. has also to be mentioned because it may contribute to ICT allowing the simultaneous transfer of proteins. 4 and Rustom et al. Several in vitro studies demonstrated that these structures make possible the exchange of molecules. These processes may represent a novel mechanism of cell– cell communication..

2004. Belting and Wittrup. They are rich in cholesterol. These ILVs are referred to as exosomes and can be released by fusion of the limiting membrane of the MVB with the plasma membrane. which contain intralumenal vesicles (ILVs) 30–100 nm in diameter. tissue culture studies show that exosomes can .2.B RA I N RE SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9 4.. but likely the mechanism is cell-to-cell communication via cell surface receptors recognizing the microvesicles (leading to signal privacy of the reserved type (see Section 1. 2008). The shedding of vesicles is preceded by the budding of small cytoplasmic protrusions. Thus. dispatched into the ECS and diffusing until the proper targets are reached (Fig. Rabs and annexins) and in MVB biogenesis (e. 2009. Microvesicles can also be formed from lipid raft domains of the plasma membrane and are then called shedding vesicles (Smalheiser. 2009). their distinct protein and lipid composition. 2008). 2005).. As far as the signals conveyed to the target cell are concerned. 2009) helps in having a classification.g. Thus. Lakkaraju and Rodriguez-Boulan... which also allow their individualization-isolation (for further details see legend to Fig. and be taken up by. 2009). Tsg101 and Alix).. 2010). but the field is still far from being described according to well accepted criteria for identification of the different classes of microvesicles. so they have the means to bind selectively to. As a matter of fact. 2008). Such a safety and privacy of the messages can only develop if the proper target cells can recognize the micro-vesicles though sets of adhesion molecules or receptors. 2008. they express certain marker proteins (e. Roamer type of VT On the basis of new data. Simons and Raposo. which are involved in endosomal-lysosomal sorting) but lack markers of lysosomes or caveolae. It cannot be excluded that exosomes merely attach to the target cell surface. As stated in Table 4. paper (Cocucci et al. As mentioned above. 3). it has been shown that intrinsic features of exosomes and of shedding vesicles allow their specific interaction with the appropriate target cells and to fulfill their task moving from the sourcecell to the target-cell(s) (Mallegol et al. It should be also noted that shedding vesicles produced by different cells contain certain proteins in common. but an alternative fate of MVBs is their exocytic fusion with the plasma membrane (Lakkaraju and RodriguezBoulan. late or recycling endosomes and. Alix and Tsg101. 2007). Thus. exosomes are microvesicles contained within a special class of endosomes. 2009).g. the “Roamer type of VT. 2009) is largely supported by experimental findings. Simons and Raposo. At their limiting membrane exosomes express some markers such as Tsg101 and CD9. Special attention has been paid so far only to exosomes and shedding microvesicles.3) that makes possible the Roamer type of VT. 2008. such as those involved in membrane trafficking (e. and lack proteins of the MVB limiting membrane (Lakkaraju and Rodriguez-Boulan. 2007. However. Several analogies may be proposed to illustrate this peculiar class of VT. One hypothesis is that the regulated release of exosomes uses similar mechanisms to those involved in the fusion of secretory lysosomes with the plasma membrane. specific recipient cell types having these sets of integrins and cell adhesion molecules. Furthermore. 2008. Exosomes are released both constitutively and in a regulated manner (Lakkaraju and Rodriguez-Boulan. 2009). Recently. the shedding vesicles contain cholesterol-rich membrane rafts. namely the pressure gradients and the temperature gradients. it may be important to underline that it often shows the important features of safety and privacy of the message. endosomes not only transport newly synthesized material from the Golgi complex and endocytosed material from the plasma membrane to various intracellular destinations. their position within the cell and the cargo that they carry.1)). Fang et al. 2007). 2006). 2008). indications have been obtained that cells can exchange not only a single message but even a set of messages (Février and Raposo. Exosomes are often released as small aggregates that could be taken up by neighboring cells via a phagocytic mechanism (leading to signal privacy of the broadcast type). exosomes are classically defined as vesicles with a diameter of 40–100 nm that originate in MVBs of the endosomal system with an emerging role as 149 intercellular signaling devices (Barral and von Herrath. they are usually classified as early.. The view that exosomes as well as shedding vesicles are safe vesicular carriers for targeted intercellular communication (Simons and Raposo. The interaction may be restricted to the plasma membrane altering the signaling of the cell or may lead to their fusion with the plasma membrane or activation of the process of endocytosis resulting in a decoding of the enclosed signals and in cell–cell communication as especially demonstrated in the immune system (Lakkaraju and Rodriguez-Boulan. which can be classified on the basis of their morphology. Endosomes are membrane-bound organelles. 2008). Simons and Raposo. 2008.. Lakkaraju and Rodriguez-Boulan image exosomes to be itinerant workers who travel away from the source of production and roam from cell to cell to disseminate important information (Lakkaraju and Rodriguez-Boulan. in particular. It has been shown that several messages can be sent via microvesicles (acting as protective containers). conferring new properties to the cell (Fang et al. However. Different types of microvesicles have been described (see Table 4 based on Cocucci et al. Schorey and Bhatnagar. sphingomyelin and ganglioside GM3.g. 5 and Guescini et al.” It is proposed that it is the vector mediated migration in VT (see Section 3.e. late endosomes are a type of multivesicular bodies (MVB). we suggest calling this type of VT.. with which some proteins are selectively associated.. These vesicles originating from the plasma membrane also express specific cell-surface proteins including integrins and cell adhesion molecules. the Cocucci et al.. This class of intercellular communication belongs according to our previously stated basic criterion to the VT mode of communication (no virtually continuous channel).. which are the result of specific cellular phenomena (for a review see Lakkaraju and Rodriguez-Boulan. Thus. oligomerization of oligomers) and which also associate with the plasma membrane are preferentially sorted into the shedding vesicles. Furthermore. (2007) proposed that proteins which exhibit higher-order oligomerization (i. Cocucci et al. which then detach by fission of their stalk. the molecular machinery involved in the exocytotic fusion of MVBs to the plasma membrane to release exosomes is still under investigation. leading to the release of the 40–100 nm ILVs (exosomes) into the extracellular milieu (Van Niel et al.

2010) (for a general panorama.150 B RA I N R E SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9 Fig. 2007). Thus. Blots were probed with antibodies against: Alix. Ultracentrifugation pellet obtained from DMEM medium with addition of 10% heat-inactivated FBS was used as a negative control. given the tentative involvement of endosomal pathways in the transmission of RNAs in lower organisms (Belting and Wittrup. however. As a matter of fact. supernatant (Sup) and whole cellular lysate proteins (Lys) from glioblastoma and astrocyte cells were separated on SDS-PAGE and electroblotted to nitrocellulose membrane.. which may be free in the medium and/or associated with the external surface of the exosome membranes. see Fig. 2008). Exosomes + Exg DNA + DNaseI = 14. Right upper panel: Mitochondrial DNA quantification from glioblastoma. 5 – Biochemical characterization of glioblastoma and astrocyte exosomes (see Guescini et al. Glioblastoma = 82. Exg DNA + DNaseI no detectable mtDNA quantity. 2007..7. Left upper panel: Schematic representation of the centrifugation steps used to isolate microvesicles released from glioblastoma and astrocyte cells. 2010).. in signaling carried out by microvesicle RNAs especially the non-coding RNAs (ncRNAs) (Valadi et al. Results: Exg DNA = 165 ± 2. Deregibus et al. which suggests that complex selection mechanisms operate during the formation or intracellular sorting of exosomal RNA (Ratajczak et al. Results: DMEM + 10% FBS no detectable mtDNA quantity. Astrocytes = 102. Of particular interest is some evidence indicating that exosomes could operate as carriers for the intercellular transfer of RNAs. 3). Guescini et al..700 ± 6000. mtDNA was isolated from exosome pellets and quantified by real-time PCR using specific primers for the mitochondrially encoded gene NADH dehydrogenase subunit 1 (MT-ND1). Burghoff et al. Left lower panel: Western blot characterization of glioblastoma and astrocyte exosomes. Intact glioblastoma-released exosomes treated with DNaseI show a marked and significant decrease in mtDNA quantity with respect to control exosomes but about 10% of mtDNA was protected from degradation.9 ± 0. contain receptors and proteins (Lakkaraju and RodriguezBoulan.75. in view of their physicochemical properties. Exosomes (Exo). and the larger fraction was present in the supernatant as “naked” mtDNA. 2007) are of a substantial interest. the results are reported as mtDNA copy number (mean ± sem. which enable these molecules to fulfill a diverse range of structural and catalytic roles through various mechanisms (Mehler and Mattick. 2008). as shown only a small fraction of mtDNA was located inside the exosomes.5 ± 0. Exogenous DNA (Exg DNA) added to the reaction was completely degraded by DNase treatment demonstrating that complete digestion had occurred. 2006. n = 6).and astrocyte-conditioned medium. The genetic material transferred to neighboring cells via exosomes. Exosomes = 100 ± 0. the results are reported as percentage with respect to exosome quantity (mean ± sem. It . gene profile analysis showed significant differences in the level of transcripts isolated from exosomes and donor cells. Molecular mass markers are shown to the left.. 2008. Tsg101 and CD9. Right lower panel: Mitochondrial DNA quantification after DNaseI treatment. Scott. does not simply mirror the transcriptional status of the donor cell. Exosomes + DNaseI = 9.75. Thus..000 ± 4700. 2007. n = 8).

the two cleaved neuropeptides are unable to bind to the neuronal opioid receptor as assessed by the cAMP response (Potolicchio et al. On the contrary. As a matter of fact. a basic question is the relevance of the Roamer type of VT for the intercellular communication in the CNS. it has been suggested (Smalheiser.. several data suggest that RNAs can propagate between cells and even between organisms (Smalheiser. As a matter of fact. It should be noticed that AMPA receptors. Exosomal secretion could likely have other physiological and pathological roles in CNS. Furthermore. On the other hand. 1977). which was so successfully exploited at the intracellular level for unicellular organisms. however. which combine to form the receptor tetramer. 2007) that exosomes born in the plasma membrane (shedding vesicles) bud from the lipid raft region of the postsynaptic membrane adjacent to the postsynaptic density. 2006). 2008. Thus. 2010) contain also mitochondrial DNA. St Laurent and Wahlestedt. for instance by supplementing the known mechanisms of anterograde and retrograde signaling across synapses. 2005). recent evidence supports a model in which the insertion of GluR1-containing receptors occurs indirectly via insertion at extra-synaptic sites followed by a lateral movement into the synaptic sites (Passafaro et al. In particular. Furthermore. which inactivates leucine. 2006).. allowing the exploration of new possible therapeutic interventions (Fiore et al. microvesicles were identified in the human cerebrospinal fluid (Marzesco et al. glycolysis and lactate transport are critical and tightly regulated functions in brain metabolism. the Roamer type of VT may greatly contribute to dynamic events of synaptic plasticity. but whole compartments of brain tissue where . As a matter of fact.. a further advantage of RNA in the context of lineage specific developmental and physiological regulation. (2008) in CSF from sheep and in these CSF-derived exosomes the authors were able to show an enrichment of prion protein over unfractionated CSF. leading to the formation of different sets of fragments from the same parent peptide and thus of different chemical networks that can modulate various CCNs eliciting different types of integrated responses (Agnati and Fuxe. the ECM is not an amorphous filling between the different cell types of the CNS. in particular both GluR1 and GluR2. On this basis we proposed that the integrative tasks of the CNS should be studied not by considering the neural networks. As a matter of fact. plays a role in the control of these two VT signals. Guescini et al. Consistent with this finding. 2006).. it has been shown that a minute fraction of Abeta peptides can be secreted from the cells in association with exosomes (Rajendran et al. 2008). 2004. 2007). provided that the microvesicle containing it can be recognized by the neuronal plasma membrane.. Taking all together. In this context it is interesting to notice that exosomes released from astrocytes and glioblastoma cells (Guescini et al.. 2008). 2005). it should be considered that the possibility of a Roamer type of VT in the CNS opens a new research field in CNS communication of high relevance for neurophysiology and neuropathology .. 2005b.. Agnati et al. play an important role in Long Term Potentiation (Whitlock et al. which could safely deliver the RNAs to the proper target cells. 2007). As far as the CNS is concerned.. 2006).. It can be surmised that exosomal CD13. On the role of the extracellular space in intercellular communication The intercellular space fulfils active tasks in the elaboration of the information since it may address the diffusion of electrochemical messages in an anisotropic fashion favoring or preventing the communication between two brain areas contributing to compartment formation.. Fuxe et al. In the context of the present paper. two possible 151 functional roles have been suggested for microglia-derived CNS exosomes. In particular. whereas homomeric GluR2 or GluR3 AMPA receptors were inserted constitutively (Whitlock et al. RNAs could transmit a range of signals to other cells without having to evolve novel signal-specific pathways. These findings open the possibility that this type of VT plays some role in the CNS. it may affect the messages released by the CNS cells. As pointed out by Dinger et al. Thus. supporting a potential role for exosomes in the pathogenesis of AD (Ghidoni et al. 2008).. for example.. exosomes were found in a study by Vella et al. The ability of microglia-derived CNS exosomes to carry out this process highlights our view of the CNS as an organized system of CCNs. exosomal MCT1 can play a role in the metabolic support to neurons. It has been shown that homomeric GluR1 AMPA receptors were functionally delivered to synapses after LTP induction. Dinger et al. and that oligodendrocytes can secrete exosomes containing myelin proteins (Lakkaraju and Rodriguez-Boulan. it can be surmised that during evolution the endosomalmediated control. Furthermore. 2007b). 2008. Actually... 2005) and in the human and rat CSF they appeared associated with a suite of signaling and intracellular proteins (Zappaterra et al. Dinger et al. (2006) demonstrated that rat and mouse cortical neurons secrete exosomes in culture. These exosomes contained two (GluR2/3) out of the four possible AMPA receptor subunits. suggesting a link between these vesicles and prion disease pathogenesis. Fauré et al. according to the Jacob's tinkering principle (Jacob. 2010). 5. can oxidize lactate for energy production and microglia could provide lactate thanks to the MCT1 transporter (Potolicchio et al. 2007.and methionine-enkephalins.. Neurons.. 2000. since they express the amino-peptidase CD13 and the lactate transporter MCT-1 (Potolicchio et al..B RA I N RE SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9 has been suggested that several classes of ncRNAs can work also as extracellular signaling molecules allowing to fully exploit their ductile and fundamental capability of regulating molecular networks (Mattick. has been used to allow efficient cell–cell communication in multi-cellular organisms. In vivo. which predominantly express isoform 1 of lactate dehydrogenase. the presence of exosomal proteins has been observed in plaques from Alzheimer's disease (AD) patient brains (Rajendran et al. in vitro studies showed that neurons can release exosomes containing glutamate receptor subunits. 2001). 2007. (2008) the endosomal machinery of signaling could be extended to include intercellular communication by taking advantage of exosomes. As far as the possible pathological role of exosomes is concerned. 2005).

2000).. Agnati and Fuxe. according to our hypothesis. ependymal cells). gap junctions. BEADS + Anti CD9 = 6. is significantly complemented by complex cellular networks (involving neurons. 2000. Although their existence and role in vivo in the CNS are still a matter of investigation and remain to be fully demonstrated. 1995c). sometimes as serial circuits and overlapping with each other at the cell membrane level. This figure shows that most of the pelleted mtDNA is free (SUPERNATANT) and only about 5% of the released mtDNA is associated with exosomes (BEADS + Anti CD9). the recently discovered new types of WT (i. the available experimental data open the possibility that the peculiar features of these intercellular communication modes could be of paramount importance for the integrative actions of the brain CCNs. 6 – Exosome purification using magnetic beads (see Guescini et al.e. 2006b. 1897. the CCN affects the GMN molecular composition and arrangements by secreting its components as well as enzymes involved in its plastic rearrangements (Rauch. astrocytes. exosomes and shedding vesicles).e.. 1906).e. also depend on the cell circuit geometry and hence on ECM characteristics. which is one of the fundamental blocks of the ECM. .1 ± 1. 2009). synaptic contacts. TNTs) and VT (i. In this respect. The extracellular part of GMN has both a scaffolding role in enabling the appropriate location of the CNS components and a functional role in cooperating to the maintenance of the microenvironment around cells and in the creation of preferential diffusion pathways. it is interesting to cite the Smalheiser's proposal (see Section 4.152 B RA I N R E SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9 different cell types and ECM work as an integrated computational unit (Agnati et al. and TNTs. As a matter of fact. a complex interplay between the molecular and topological organization of the GMN and the intercellular WT and VT occurs to establish the optimal tuning of the CNS integrative actions.. 1914). the CNS is a computational system with two computing nets. which enmeshes the entire CNS (Apathy. In this context. Fuxe and Agnati. of particular interest are. Results: SUPERNATANT = 100 ± 6..e. This enlarged view is in agreement with Golgi's proposal that can be paraphrased by stating that different brain cells (neurons and glial cells) present in a certain brain region can operate as a single integrative “province” (Golgi.. 2004). signal diffusion and convection) including the Roamer type of VT is affected by the control of the net tightness of the ECM meshes and by the medium fluidity. It is obvious that intercellular VT (i. especially from the post-synaptic dendrite to the pre-synaptic terminal can play a role in synaptic plasticity (Smalheiser. CD9 antibodies were used in the binding of exosomes to the beads followed by magnetic immunoprecipitation. working sometimes as parallel circuits. the CCN and the GMN. in our opinion. ECM characteristics modulate the formation and the maintenance of these subclasses of intercellular communication. This signaling backbone. In this way the hyaluronan-lectican-tenascin R model of the brain ECM was introduced.. In turn. the results are reported as percentage with respect to SUPERNATANT quantity (mean ± sem. oligodendroglial cells.. microglial cells. Left panel: mtDNA was quantified from glioblastoma-released exosome fraction after purification with magnetic beads. Thus. 2010). i. which alter the tortuosity of the diffusion pathways (Nicholson et al. Fig. Elements of these networks communicate basically via two classes of connections (WT and VT).65. 6. Concluding remarks Brain integrative action mainly depends on neural networks and on the synaptic transmission (Sherrington. Agnati et al. n = 3). Right panel: Quantification of mtDNA present within purified exosomes. A model of the meshes of the ECM has been proposed by Yamaguchi (Yamaguchi. however. 2000) where VT signals including exosomes released by the source cell migrate to reach the target cells. It has also been proposed that beside the CCNs also the molecular networks formed by organized elements of the ECM should be considered and that these molecular networks mainly made by proteins and carbohydrates interact with the cell membrane molecular networks to form a “global molecular network” (GMN). 2007). Thus.. can form meshes of different tightness.2) that exosomal transfer of proteins and RNAs. who suggested that hyluronan. It should be noticed that all the subclasses of the intercellular WT.

2010). mtDNA has been demonstrated in samples of liquors of subjects with hydrocephalus or aqueductal stenosis and in controls (Fuxe et al. Thus. 8 and Fuxe et al.001. Mitochondrial DNA (mtDNA) content from liquor samples was measured by real-time PCR using specific primers for the mitochondrially encoded genes: NADH dehydrogenase subunit 1 (MT-ND1). Thus. These data led us to hypothesize that higher liquor pressures may cause the rupture of tunnelling nanotubes with mitochondria leaking mtDNA into the extracellular space. .2) can allow the transfer of mtDNA (as TNTs can do in some instances. It should also be mentioned that both classical VT (see Section 3 and Figs. Two possible mechanisms for mtDNA diffusion and/or flow in the extracellular fluid and hence in the liquor are illustrated (see Fig. 8 – In vivo studies on mitochondrial DNA in liquor in human subjects Through mitochondrial DNA (mtDNA) quantification from liquor of human subjects it has been shown that mtDNA may migrate in vivo as a possible VT signal. mtDNA quantification from liquor supports the view that mtDNA can operate as a VT signal. It is surmised that mtDNA detected in the liquor of control subjects could depend on either on a release process of mtDNA from cells and/or exosomes or on the rupture of tunnelling nanotubes with diffusion into the extracellular space of their content including mtDNA. NADH dehydrogenase subunit 4 (MT-ND4) and cytochrome oxidase subunit 1 (MT-CO1). Kruskal–Wallis test). Hence. 2010). Mitochondrial DNA was isolated from 200 μl (microliter) of liquor using the Qiamp Mini kit (Qiagen) according to the manufacturer’s instructions. but also genetic information (mtDNA and RNA) and even entire cell organelles (see Section 4. Thus. see also Fig. 7 – Schematic representation of migration of mitochondria and mtDNA via WT (TNTs) and classic (regular) and Roamer type of VT. a situation like the one shown in Fig. sem = 5 years) affected by chronic migraine underwent to a battery of clinical investigations and also to the examination of their liquor.1).B RA I N RE SE A R CH RE V I EW S 64 ( 20 1 0 ) 1 3 7–1 5 9 153 Fig. 7 is very likely. it is of great importance to realize that intercellular communication can involve not only transmitters and electrical (ionic) signals. 5 and 6) and the Roamer type of VT (see Section 4. Six control subjects (average age years = 46. Fig. 8). 4). Further support for such a view has been obtained by analyzing liquor from human beings (see Fig. Aqueductal stenosis but not hydrocephalus produces a substantial and significant rise of the mtDNA number for the three mitochondrial genes studied (p < 0.. Mean mtDNA copy number per ml liquor is shown in relation to controls..

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