Review TRENDS in Neurosciences
INMED/TINS special issue
Role of GABAergic inhibition in
hippocampal network oscillations
Edward O. Mann and Ole Paulsen
Department of Physiology, Anatomy and Genetics, Parks Road, Oxford, OX1 3PT, UK
Physiological rhythmic activity in cortical circuits relies on
GABAergic inhibition to balance excitation and control
spike timing. With a focus on recent experimental pro-
gress in the hippocampus, here we review the mechan-
isms by which synaptic inhibition can control the precise
timing of spike generation, by way of effects of GABAergic
events on membrane conductance (‘shunting’ inhibition)
and membrane potential (‘hyperpolarizing’ inhibition).
Synaptic inhibition itself can be synchronized by way of
interactions within networks of GABAergic neurons, and
by excitatory neurons. The importance of GABAergic
mechanisms for generation of cortical rhythms is now
well established. What remains to be resolved is how such
inhibitory control of spike timing can be harnessed for
long-range fast synchronization, and the relevance of
these mechanisms to network function. This review is
part of the INMED/TINS special issue Physiogenic and
pathogenic oscillations: the beauty and the beast, based
on presentations at the annual INMED/TINS symposium
(http://inmednet.com).
Introduction
A principal feature of cortical network organization is
massive recurrent excitation [1]. Similar to networks of
neurons forming central pattern generators in the brain
stem and spinal cord [2], cortical networks can generate
rhythmic activity through mutual excitation [3], which, if
left unchecked, can produce massive synchronous dis-
charges that are the hallmark of epilepsy [4]. The gener-
ation of physiological cortical rhythms depends upon
synaptic GABAergic inhibition to balance excitation [5]
and control the millisecond precision of spike timing [6–
8]. The fact that these cortical network oscillations vary
with the behavioural state of the animal has led to many
suggestions for their role in cognitive processing, but it still
remains unclear whether rhythmic synchronization in
cortical circuits serves an independent computational func-
tion [9].
To understand what function oscillations have in the
brain, it might be necessary to first consider the mechan-
isms underlying their generation. Network oscillations
require regular and temporally coordinated spike gener-
ation in the population of neurons forming the circuitry,
and the mechanisms by which this can be achieved have
Corresponding author: Paulsen, O. (ole.paulsen@dpag.ox.ac.uk).
Available online 25 May 2007.
www.sciencedirect.com 0166-2236/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2007.05.003
Vol.30 No.
been particularly well studied in the hippocampus. Here,
we discuss the mechanisms by which GABAergic events
can control spike timing in individual neurons, how GABA-
ergic interneurons incorporated within the hippocampal
circuit can act to synchronize network activity and, finally,
what consequences such synchronization might have for
network function.
Control of spike timing in individual neurons
Several factors influence the way in which GABAergic
mechanisms control spike timing, including the nature
and time course of the conductance changes that are
effected in the neuronal membrane [10], their interaction
with the intrinsic membrane properties of the neuron [7],
and the subcellular membrane domain of the synaptic
contact(s) [11].
GABA receptors underlying synaptic inhibition
Most inhibitory synapses in the brain use
gamma-aminobutyric acid (GABA) as a transmitter.
Synaptically released GABA acts via two main types of
receptor: the ionotropic GABAA receptors and the metabo-
tropic GABAB receptors (Figure 1a). The GABAA receptors
directly control the gating of ion channels permeable to
chloride and bicarbonate ions. They cluster at synaptic
release sites, where they produce synaptic conductances
with fast rise and decay kinetics and mediate phasic
inhibition. GABAA receptors are also expressed in the
extrasynaptic membrane, where they are sensitive to
the ambient levels of GABA in the extracellular space,
and give rise to a tonic inhibitory conductance. The con-
centration of extracellular GABA depends on synaptic
spillover and the activity of GABA transporters; thus,
the degree of network activity can modulate tonic inhi-
bition, which affects the input–output relationship of the
neuron by changing the input conductance and membrane
time constant [12].
GABAB receptors are located both pre- and
postsynaptically, where their major respective roles appear
to be in regulating transmitter release by inhibiting Ca2+
channels, and mediating slow inhibitory conductances last-
ing hundreds of milliseconds through the activation of
inwardly rectifying K+ channels (Figure 1a,b). The acti-
vation of GABAB receptors can also have more complex
effects, including the modulation of intracellular signa-
lling cascades and, therefore, there are many pathways
by which GABAB receptor-mediated inhibition can
344 Review TRENDS in Neurosciences Vol.30 No.7

Figure 1. Control of spike timing by shunting and hyperpolarizing inhibition. (a) GABAergic synapse with postsynaptic ionotropic GABAA receptors permeable to Cl and
HCO3 at synaptic and extrasynaptic locations, and pre- and postsynaptic metabotropic GABAB receptors, coupled by way of G-proteins to Ca2+ and K+ channels. (b) Spatial
distribution of GABAergic synapses. Presynaptic inhibition is mediated by way of GABAB receptors, and postsynaptic dendritic inhibition is mediated by both GABAA and
GABAB receptors. By contrast, inhibition at perisomatic sites appears to be mediated exclusively by GABAA receptors. (c) Kinetics of GABAA receptor-mediated events. The
synaptic conductance change (Gsyn) responsible for shunting is short lasting, whereas the time course of the associated membrane potential effect is determined by the
membrane time constant of the postsynaptic neuron. The effect on membrane potential can be depolarizing, hyperpolarizing or clamping, depending on the relation
between the actual membrane potential (Vm) and the reversal potential of the GABAA receptor-gated conductance (Esyn). (d) The effect of shunting and hyperpolarization on
spike generation. To emphasize the distinct effects of changes in membrane conductance and membrane potential produced by GABAergic events, this example uses
model cells that display intrinsic oscillations driven by a T-type calcium current, which can be observed in several subcortical nuclei. Whereas pure shunting can only veto
the generation of an action potential within a brief time window, hyperpolarizing inhibition can also phase reset the oscillation. The interaction between hyperpolarizing
inhibition and the T-type calcium current also increases transiently the number of spikes per cycle, which is an example of rebound excitation. (e) Example of rate
homogenization and phase synchronization by GABAergic events. The effect of having the reversal potential of the GABAA receptor-gated conductance within the range of
membrane potential fluctuations is explored in a set of three model cells displaying simple Hodgkin–Huxley kinetics, and receiving different levels of tonic excitatory drive.
Owing to the clamping effect on membrane potential, following the introduction of rhythmic GABAergic events, both rate and phase of firing is immediately homogenized
between the three neurons [70].

powerfully modulate neuronal activity and plasticity [13].
Nevertheless, the natural conditions under which GABAB
receptors are activated and participate in network synchro-
nization have been thoroughly explored only in the
thalamus (reviewed in Ref. [14]).
Shunting and hyperpolarizing inhibition
Both GABAA and GABAB receptor-mediated events have
two effects on the postsynaptic membrane. One is a
shunting effect owing to an increase of the postsynaptic
membrane conductance, and the other is a change in the
membrane potential owing to the current flowing through
this conductance. The pure shunting effect is always
inhibitory, as it acts to reduce the membrane depolarizing
effect of concurrent excitatory events [15], but can only be
studied in isolation when the membrane potential
remains at a relatively stable subthreshold level that is
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the same value as the reversal potential for the inhibitory
conductance. This shunting effect lasts for only as long as
the ion channels mediating the inhibitory event remain
open, which might be as brief as a few milliseconds
[the decay time constant of unitary GABAA receptor-
mediated inhibitory postsynaptic currents (IPSCs) in
basket cells is 2 ms [16]; Figure 1c]. In a fully active
neuronal network, the spatiotemporal pattern of multiple
inhibitory events would determine the overall magni-
tude and time course of the phasic shunting effect. Any
effects that outlast these conductance changes must be
due to the accompanying effects on membrane potential.
The term ‘shunting inhibition’ is often used to refer to any
inhibitory event with a reversal potential within the
range of membrane potential fluctuations, and thus
includes its effect on both the membrane conductance
and membrane potential [17].
 Review TRENDS in Neurosciences
The GABAergic current can be hyperpolarizing or
depolarizing depending on the reversal potential of the
synaptic conductance relative to the actual membrane
potential (Figure 1c). Whereas postsynaptic GABAB re-
ceptor-mediated events are always hyperpolarizing, the
relationship between the GABAA reversal potential and
the neuronal membrane potential varies across develop-
ment, behavioural state and neuronal subtype. In imma-
ture cortical neurons, the GABAA reversal potential is
typically positive to the resting membrane potential, lead-
ing to depolarizing GABAA receptor-mediated events,
which might help to drive network activity [18]. By con-
trast, in mature cortical pyramidal neurons, the reversal
potential of the GABAA receptor current is usually in the
range of 60 to 75 mV owing to the action of the K+/Cl
co-transporter KCC2, whose expression increases over the
course of development [18,19]. In quiescent in vitro prep-
arations, and during the hyperpolarized states of slow-
wave sleep, this GABAA reversal potential can still be
positive compared with the resting membrane potential
and, under these conditions, GABAA receptor activation
would be depolarizing. However, during active network
states, GABAA receptor activation will typically lead to
hyperpolarization in pyramidal neurons (Figure 1c,d).
By contrast, both hyperpolarizing and depolarizing
GABAA receptor-mediated events might have a role in con-
trolling spike timing in GABAergic interneurons during
active network states, as the GABAA reversal potential is
often less negative than in pyramidal neurons and is close to
the threshold for action potential generation [20]. This is
because the expression of KCC2 in at least some classes of
GABAergic interneurons appears not to increase over post-
natal development [21]. In GABAergic interneurons, there-
fore, the main effects of fast GABAergic events might be
‘shunting inhibition’, which would enable higher spike rates,
combined with a virtual clamping of the membrane poten-
tial close to spike threshold, which would increase the
regularity and precision of spike timing and homogenize
firing rates (Figure 1e) [17,20].
Interactions between GABAergic events and intrinsic
voltage-dependent conductances
When inhibitory events are hyperpolarizing, they can
paradoxically excite neurons by interacting with intrinsic
voltage-dependent conductances, and producing anode-
break or ‘rebound’ excitation [7,22] (Figure 1d). This effect
of membrane hyperpolarization can be mediated by acti-
vating inward (depolarizing) currents, such as IH, by deac-
tivating outward (hyperpolarizing) currents, such as IM, or
by deinactivating inward currents, such as Na+ and Ca2+
currents. The rebound spike phenomenon can contribute to
the control of spike timing [7].
Differential roles of perisomatic and dendritic
inhibition in controlling pyramidal cell spiking
The way in which GABAergic neurons can affect spike
timing also depends on the specific subcellular membrane
domains onto which they synapse. Basket cells and axo-
axonic cells, which selectively target the perisomatic
domain and whose postsynaptic sites are devoid of GABAB
receptors, have the ability to gate precisely the timing of
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Vol.30 No.7 345
action potential generation [7,23,24] (Figure 1b,e). By
contrast, synaptic inhibition from dendritic-targeting cells
exerts weaker direct control over spike timing, as the
resulting inhibitory postsynaptic potentials (IPSPs) at
the site of spike generation have smaller amplitudes and
slower kinetics owing to electrotonic filtering and, possibly,
differences in the subunit composition of the GABAA recep-
tors [25]. Dendritic inhibition thus appears more suited to
local control of the communication between dendrites
and soma by way of shunting co-aligned excitatory inputs
and by modulating both action potential back-propagation
and dendritic electrogenesis [11,23]. However, dendritic
inhibition could also have subthreshold interactions with
dendritic voltage-dependent currents, such as IH, and ther-
eby have delayed indirect effects on spike timing. Indeed,
whereas perisomatic-targeting interneurons have been
reported to be specifically involved in the synchronization
of fast network oscillations [24,26], dendritic-targeting
cells might have a more intimate role in the pacing of
slower network rhythms [27].
In summary, although all aspects of GABAergic
transmission contribute to modulating neuronal excit-
ability, its role in controlling the millisecond precision of
spike timing can largely be understood in terms of GABAA
receptor-mediated phasic hyperpolarizing inhibition in
pyramidal neurons and phasic ‘shunting inhibition’ in
GABAergic interneurons.
GABAergic interactions in cortical networks
Individual GABAergic neurons do not act independently to
affect spike timing; therefore it is necessary to address how
they interact with other neurons to coordinate rhythmic
population activity. GABAergic neurons are embedded in
local interneuronal networks, and are connected by both
chemical [28–30] and electrical synapses (gap junctions)
[30,31], and also receive common recurrent excitation
[28]. Local interneuronal networks have the potential to
generate oscillations over a wide range of frequencies. These
oscillations can control spike timing in pyramidal neurons,
which, again, can entrain their downstream targets [32,33].
Why would evolution select inhibition, rather than
excitation, for the control of spike timing? The extensive
dendritic tree of pyramidal neurons makes them suitable
for temporal integration, further shaped by numerous
dendritic voltage-dependent conductances. By contrast,
many interneurons are comparatively electrotonically
compact, with rapid integration time constants and, con-
sequently, can fire action potentials in response to the
same excitatory input with much improved temporal pre-
cision compared with pyramidal neurons [34,35]. More-
over, the strategic placement of their inhibitory synaptic
output close to the spike initiation zone of pyramidal cells
gives fast-spiking perisomatic-targeting interneurons
exquisite control of pyramidal cell spike generation, with
little effect on dendritic integration [23]. Thus, one might
envisage a division of labour between dendritic excitation
and inhibition on one hand, and perisomatic inhibition on
the other, in slowly modulating firing rate and controlling
the precision of spike timing, respectively. In the following,
the role of interneurons in generation, propagation, and
mutual synchronization of cortical oscillations is discussed.
346 Review TRENDS in Neurosciences Vol.30 No.7

Generation of fast oscillations
Whereas there is general agreement that GABAergic
interneurons are important for hippocampal fast network
oscillations [7,36,37] (reviewed in Refs [17,38]), the mech-
anisms that control the spike timing of interneurons are
still debated. The first and simplest mechanism proposed
for the control of interneurons during fast oscillations was
an excitatory–inhibitory feedback loop [39] (Figure 2a).
Several decades later, it was suggested that an interneur-
onal network could independently generate such oscil-
lations [36] (Figure 2a). It is now commonly assumed
that both these mechanisms are involved in the generation
of physiological oscillations, but their relative importance
might vary between brain areas.
GABAergic neurons innervate not only excitatory cells,
but also themselves and each other (Figure 2a). Such
GABAergic self-innervation can increase the regularity
and precision of spike timing, and enable the generation
of oscillations within interneuronal networks [17,36].
Although inhibitory loops between cortical and subcortical
GABAergic neurons could have a role in slow rhythms,
such as hippocampal theta-frequency oscillations [40],
most research has focused on the involvement of local
interneuronal networks in the synchronization of fast
oscillations in hippocampal circuits [17,38].
One problem in understanding the mechanisms
underlying such interneuronal synchronization is that
interneurons display an array of cellular and synaptic
properties, and yet computational studies have shown that
fast oscillations based on reciprocal inhibition are exqui-
sitely sensitive to heterogeneities in the network [17,41].
This problem is simplified at a conceptual level by the fact
that distinct interneuronal subtypes, which share similar
physiological characteristics, synchronize together and
display segregated firing patterns from other interneuron
types [42]. Indeed, although many subtypes of interneuron
can be recruited to local fast network oscillations, periso-
matic-targeting interneurons appear to be particularly
important for the actual rhythm generation [24,26,43].
Such cell-selective synchronization could be sharpened
by electrical gap junction coupling between interneurons,
which appears to be restricted to members of the same
interneuronal subtype [31]. Further robustness against
variability within cell classes might be achieved by shunt-
ing inhibition between GABAergic neurons, which would
not only enable fast synchronization, but also tend to
homogenize firing rates between cells [20] (Figure 1e).
GABAergic interneurons also receive strong recurrent
phasic excitation from pyramidal cells [44], and by varying
the balance between the excitatory and inhibitory mechan-
isms controlling interneuron spike timing, local networks
could potentially support oscillations over a wide variety of
frequencies, from beta (13–30 Hz) to fast ripple frequencies
(140–200 Hz). Indeed, theoretical studies suggest that a
network of purely inhibitory neurons can sustain oscillation
frequencies up to 200 Hz, with increasing involvement of
excitatory neurons causing a progressively slower rhythm
[45]. In this context, there might not be a consistent relation-
ship between the label under which a given oscillation
frequency is classified, and the underlying cellular mech-
anisms. For example, both interneuronal networks and
feedback loops between pyramidal cells and interneurons
can generate network oscillations in the gamma-frequency
band [24,36,37]. However, considering the rapid kinetics of
recurrent GABAergic synapses, and the fact that feedback
loops between pyramidal neurons and interneurons also
involve slower GABAergic synapses in addition to the extra
delays associated with synaptic excitation, it is possible that
pyramidal–interneuron coupling is involved in generating
beta- and low gamma-frequency oscillations, whereas high
gamma-frequency cortical oscillations (80–140 Hz) might
depend on interneuronal networks escaping from phasic
excitation, and have more in common with hippocampal
ripple-frequency oscillations [46].
Propagation of oscillations
In the intact brain, a large number of network oscillators
coexist, which interact with each other through competition
and transient coupling. The dynamic coupling and uncou-
pling of distant neural sites have been suggested to reflect
changes in communication between these sites [47]. The
mechanisms by which temporal patterns of activity are
propagated might vary with frequency. Indeed, whereas
the downstream recruitment of excitatory pyramidal
neurons is an efficient means for slow oscillations to travel
across the neocortex [48], the propagation of fast hippo-
campal oscillations is likely to depend on the synchroniza-
tion of interneurons in the target region (Figure 2b). A well
studied example is the propagation of gamma-frequency
oscillations from CA3 to CA1 of hippocampus [24,33]. The

Figure 2. Neuronal circuits for short- and long-range synchronization of GABAergic inhibitory networks. (a) Mechanisms of local synchronization by GABAergic
interneurons. Two main models have been proposed: (i) an excitatory–inhibitory (E–I) feedback loop, and (ii) an independent interneuronal network interconnected by
inhibitory synapses and gap junctions (illustrated by a resistor symbol). (b) Propagation of fast oscillation. Downstream synchronization is mediated most effectively via
excitatory connections onto GABAergic interneurons (solid line), rather than excitatory–excitatory connections (dashed line). (c) Long-range synchronization could be
achieved by the phase resetting of local oscillators through mutual excitation and/or a common excitatory input. (d) Long-range synchronization by inhibition. The
existence of GABAergic neurons that display long-range projections that selectively target other interneurons offers the additional possibility for long-range
synchronization of fast local oscillators by mutual inhibition. Excitatory neurons are shown in black, inhibitory neurons in red.

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 Review TRENDS in Neurosciences Vol.30 No.7 347

reason that interneurons are the preferred mediators remains debated, with ideas for their relevance ranging
of such fast entrainment again derives from the stronger from mere epiphenomenon to crucial for information pro-
and more precise excitatory postsynaptic potential (EPSP)- cessing. It is not yet clear how these hypotheses can be
spike coupling in many interneuron subtypes compared tested experimentally, as it has been difficult to disrupt
with pyramidal cells [34], enabling high-frequency infor- selectively the temporal coordination of network activity
mation to be preserved. without affecting spike rates. As a first approach, we can
ask the question, if oscillations are mediated by rhythmic
Long-range fast synchronization inhibitory activity, what are the functional implications for
Many distinct brain regions are reciprocally connected; hippocampal neurons? Inhibitory rhythms confer two main
thus, it is important not only to understand how oscil- interrelated properties on the local network, which could
lations propagate, but also if and when local rhythms can be harnessed for distinct functions: (i) the synchronization
mutually synchronize. This has received particular atten- of principal neuron spiking, and (ii) the regular and syn-
tion in the neocortex, where it has been suggested that chronous occurrence of background membrane potential
long-range synchronization can occur at beta- and gamma- fluctuations in the local population of neurons. Function-
frequencies with zero phase-lag across regions separated ally, these properties could be exploited by downstream
by significant axonal conduction delays, and even across areas by using coincidence detectors to recognize spike
hemispheres [49]. If two distant cortical networks inde- synchrony among upstream elements, or by using the
pendently generate beta- or gamma-frequency oscillations, rhythmic inhibition as a common reference signal for
the simplest mechanism to synchronize their activity temporal coding.
would be a common external input that resets the phase The synchronization of spiking in presynaptic principal
of the local oscillations (Figure 2c). The cellular properties neurons has been proposed to enhance the efficiency of
of interneurons would again make them the most effective signal propagation through the network [47] (Figure 3a);
recipient of such a phase-resetting signal [34], and the thus, the degree of spike synchrony between cells might
common external input would only have to be transient or encode another layer of information in addition to that
intermittent to yield near synchrony over many cycles. conveyed by spike rates. Spike synchrony does not require
However, it has also been suggested that long-range oscillations, but it has been argued that synchronization is
phase-coupling can be achieved with only reciprocal con-
nections. It is difficult to explain theoretically how zero
phase-lag long-range synchronization could occur when
there are significant conduction delays in the connections
between the oscillating networks [50,51]. One elegant
proposed solution is based on strong reciprocal long-range
excitatory projections onto local interneurons (Figure 2c),
which enables the distal inputs to evoke a delayed second
spike on each oscillatory cycle, and thus produce a con-
tinuous phase reset of the local rhythms. However, such
doublet spiking in interneurons naturally lowers the fre-
quency of the oscillations, and only appears to explain
synchronization in the beta-frequency range [52]. How-
ever, although less frequent, some classes of GABAergic
neurons also show long-range projections and selectively
target other interneurons [53,54]. It is possible that fast
synchronization is mediated through reciprocal long-range
inhibition [55] (Figure 2d), without the need for doublet
spiking. Unfortunately, little data are available from ana-
tomically identified neurons in vivo to inform compu-
tational models in this field, and such experimental data
are urgently required if we are to solve the problem of long-
range synchronization.
In summary, the study of the cellular and synaptic basis
of network synchronization in vivo, in reduced in vitro
preparations and in computational models has enabled a
detailed understanding of the mechanisms contributing to
Figure 3. Functional consequences of synchronized inhibition. (a) Coding by
the generation of local hippocampal oscillations. However, synchrony. If two excitatory cells (black) display random (‘Poisson’) spike trains,
we have more limited insights into why, when, and where they will rarely drive a common downstream coincidence detector target above
each of these different mechanisms predominates, and how threshold (grey). By contrast, when synchronized by an inhibitory interneuron
(red), these neurons, firing at the same overall rate, will now reliably activate the
distributed local oscillators interact. downstream target. (b) Oscillatory phase encoding. If five pyramidal neurons
(black) are firing at different rates, the introduction of a rhythmic inhibitory
Functional consequences of rhythmic inhibition oscillation will produce a rate-to-phase transform for the first spike in each cycle as
an inescapable consequence of biophysical properties of integrate-and-fire
Oscillations are a prominent feature of hippocampal neurons. The sloping red line indicates the range of phase encoding possible by
network activity, but the functional role of these rhythms this mechanism in passive neurons.

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348 Review TRENDS in Neurosciences
assisted by oscillatory properties of neuronal elements
[56]. It has been suggested that oscillatory synchrony
functions to bind together different attributes of a sensory
percept or a memory item [57,58]. Unfortunately, without a
better understanding of the synaptic origin of synchroniza-
tion, and how distributed neurons encoding different
stimulus attributes could selectively oscillate together, it
is difficult to evaluate what such synchronization reveals
about brain processing.
A fundamentally different coding scheme is offered by
utilizing rhythmic inhibition as a time base for phase
encoding. In this scenario, it is not the synchronized
elements that take part in encoding, but rather those
elements that escape the synchrony. The possibility that
such a coding scheme might be implemented in the brain
was suggested by the finding that spike timing of hippo-
campal pyramidal neurons relative to ongoing theta oscil-
lations provides information about the location of an
animal [59]. More specifically, for animals running on a
linear track, the firing phase of the neuron moves progress-
ively forwards as the animal moves through the place field
of that neuron, producing a phenomenon termed ‘phase
precession’ [59,60]. How the firing phase is controlled has
been vigorously discussed, with ideas of its origin ranging
from a simple rate-to-phase transform [61,62] to a separate
coding domain independent of firing rate [59,63]. At a basic
cellular level, it is clear that spike timing within imposed
theta oscillations is dependent on the tonic input to a
neuron [64] (Figure 3b), but spikes can be further advanced
or delayed by phasic synaptic input [65]. Oscillatory phase
encoding has attractive computational properties [66] and
can temporally compress sequences at behavioural time-
scales into spike sequences within individual oscillatory
cycles, and thus set the conditions for information to be
stored by spike timing-dependent plasticity [60].
Obviously, these two schemes are not mutually exclusive,
and it is even possible that they exist in parallel. For
example, fast synchrony could be encoded superposed on
a slower rhythm, as suggested in models of hippocampal
sequence encoding during theta-nested gamma oscillations
[58,67]. Indeed, recent evidence suggests that local inter-
neurons can follow the theta phase precession of the pyr-
amidal cells that drive them [68,69], thus enabling a local
fast oscillation to emerge superposed on the more distrib-
uted theta oscillation, consistent with the local nature of fast
and more global nature of slow oscillations [40,56].
Conclusion
With their convergent fast and strong excitatory and
inhibitory synaptic inputs, rapid membrane time con-
stants and divergent fast and strong output, fast spiking
interneurons appear well suited for a role in fast oscillatory
synchronization. Although we are beginning to understand
the mechanisms underlying generation and propagation of
simple inhibitory-based network oscillations, we are still
far from understanding how different network oscillators
interact and what computations are achieved with these
interactions. Understanding the mechanisms underlying
network oscillations might not only inform computational
modelling, but will hopefully also make it possible to
develop experimental tools that can selectively disrupt
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Vol.30 No.7
oscillatory activity, and enable experimental evaluation
of the causal relations between oscillatory activity and
cognitive processes.
Acknowledgements
We thank the Wellcome Trust and the Biotechnology and Biological
Sciences Research Council, UK, for supporting our research. We thank
the reviewers for useful comments on an earlier version of the article.
References
1 Somogyi, P. et al. (1998) Salient features of synaptic organisation in the
cerebral cortex. Brain Res. Brain Res. Rev. 26, 113–135
2 Grillner, S. (2006) Biological pattern generation: the cellular and
computational logic of networks in motion. Neuron 52, 751–766
3 Steriade, M. et al. (1993) A novel slow (<1 Hz) oscillation of neocortical
neurons in vivo: depolarizing and hyperpolarizing components. J.
Neurosci. 13, 3252–3265
4 Dichter, M.A. and Ayala, G.F. (1987) Cellular mechanisms of epilepsy:
a status report. Science 237, 157–164
5 Shu, Y. et al. (2003) Turning on and off recurrent balanced cortical
activity. Nature 423, 288–293
6 Buzsaki, G. and Chrobak, J.J. (1995) Temporal structure in spatially
organized neuronal ensembles: a role for interneuronal networks. Curr.
Opin. Neurobiol. 5, 504–510
7 Cobb, S.R. et al. (1995) Synchronization of neuronal activity in
hippocampus by individual GABAergic interneurons. Nature 378,
75–78
8 Fricker, D. and Miles, R. (2001) Interneurons, spike timing, and
perception. Neuron 32, 771–774
9 Sejnowski, T.J. and Paulsen, O. (2006) Network oscillations: emerging
computational principles. J. Neurosci. 26, 1673–1676
10 Nicoll, R.A. (1988) The coupling of neurotransmitter receptors to ion
channels in the brain. Science 241, 545–551
11 Buhl, E.H. et al. (1994) Diverse sources of hippocampal unitary
inhibitory postsynaptic potentials and the number of synaptic
release sites. Nature 368, 823–828
12 Semyanov, A. et al. (2004) Tonically active GABA A receptors:
modulating gain and maintaining the tone. Trends Neurosci. 27,
262–269
13 Scanziani, M. (2000) GABA spillover activates postsynaptic GABAB
receptors to control rhythmic hippocampal activity. Neuron 25, 673–
681
14 Steriade, M. (2005) Sleep, epilepsy and thalamic reticular inhibitory
neurons. Trends Neurosci. 28, 317–324
15 Staley, K.J. and Mody, I. (1992) Shunting of excitatory input to dentate
gyrus granule cells by a depolarizing GABAA receptor-mediated
postsynaptic conductance. J. Neurophysiol. 68, 197–212
16 Bartos, M. et al. (2001) Rapid signaling at inhibitory synapses in a
dentate gyrus interneuron network. J. Neurosci. 21, 2687–2698
17 Bartos, M. et al. (2007) Synaptic mechanisms of synchronized gamma
oscillations in inhibitory interneuron networks. Nat. Rev. Neurosci. 8,
45–56
18 Ben-Ari, Y. (2002) Excitatory actions of GABA during development: the
nature of the nurture. Nat. Rev. Neurosci. 3, 728–739
19 Rivera, C. et al. (1999) The K+/Cl co-transporter KCC2 renders GABA
hyperpolarizing during neuronal maturation. Nature 397, 251–255
20 Vida, I. et al. (2006) Shunting inhibition improves robustness of gamma
oscillations in hippocampal interneuron networks by homogenizing
firing rates. Neuron 49, 107–117
21 Banke, T.G. and McBain, C.J. (2006) GABAergic input onto CA3
hippocampal interneurons remains shunting throughout development.
J. Neurosci. 26, 11720–11725
22 Andersen, P. and Eccles, J. (1962) Inhibitory phasing of neuronal
discharge. Nature 196, 645–647
23 Miles, R. et al. (1996) Differences between somatic and dendritic
inhibition in the hippocampus. Neuron 16, 815–823
24 Mann, E.O. et al. (2005) Perisomatic feedback inhibition underlies
cholinergically induced fast network oscillations in the rat
hippocampus in vitro. Neuron 45, 105–117
25 Mody, I. and Pearce, R.A. (2004) Diversity of inhibitory
neurotransmission through GABAA receptors. Trends Neurosci. 27,
569–575
 Review TRENDS in Neurosciences
26 Hajos, N. et al. (2004) Spike timing of distinct types of GABAergic
interneuron during hippocampal gamma oscillations in vitro. J.
Neurosci. 24, 9127–9137
27 Gloveli, T. et al. (2005) Differential involvement of oriens/pyramidale
interneurones in hippocampal network oscillations in vitro. J. Physiol.
562, 131–147
28 Freund, T.F. and Buzsaki, G. (1996) Interneurons of the hippocampus.
Hippocampus 6, 347–470
29 Cobb, S.R. et al. (1997) Synaptic effects of identified interneurons
innervating both interneurons and pyramidal cells in the rat
hippocampus. Neuroscience 79, 629–648
30 Fukuda, T. and Kosaka, T. (2000) The dual network of GABAergic
interneurons linked by both chemical and electrical synapses: a
possible infrastructure of the cerebral cortex. Neurosci. Res. 38, 123–130
31 Fukuda, T. and Kosaka, T. (2000) Gap junctions linking the dendritic
network of GABAergic interneurons in the hippocampus. J. Neurosci.
20, 1519–1528
32 Csicsvari, J. et al. (1999) Fast network oscillations in the hippocampal
CA1 region of the behaving rat. J. Neurosci. 19, RC20
33 Csicsvari, J. et al. (2003) Mechanisms of gamma oscillations in the
hippocampus of the behaving rat. Neuron 37, 311–322
34 Fricker, D. and Miles, R. (2000) EPSP amplification and the precision of
spike timing in hippocampal neurons. Neuron 28, 559–569
35 Jonas, P. et al. (2004) Interneuron Diversity series: Fast in, fast out –
temporal and spatial signal processing in hippocampal interneurons.
Trends Neurosci. 27, 30–40
36 Whittington, M.A. et al. (1995) Synchronized oscillations in
interneuron networks driven by metabotropic glutamate receptor
activation. Nature 373, 612–615
37 Fisahn, A. et al. (1998) Cholinergic induction of network oscillations at
40 Hz in the hippocampus in vitro. Nature 394, 186–189
38 Whittington, M.A. and Traub, R.D. (2003) Interneuron diversity series:
inhibitory interneurons and network oscillations in vitro. Trends
Neurosci. 26, 676–682
39 Freeman, W.J. (1968) Relations between unit activity and evoked
potentials in prepyriform cortex of cats. J. Neurophysiol. 31, 337–348
40 Buzsaki, G. (2002) Theta oscillations in the hippocampus. Neuron 33,
325–340
41 Wang, X.J. and Buzsaki, G. (1996) Gamma oscillation by synaptic
inhibition in a hippocampal interneuronal network model. J.
Neurosci. 16, 6402–6413
42 Klausberger, T. et al. (2003) Brain-state- and cell-type-specific firing of
hippocampal interneurons in vivo. Nature 421, 844–848
43 Fuchs, E.C. et al. (2007) Recruitment of parvalbumin-positive
interneurons determines hippocampal function and associated
behavior. Neuron 53, 591–604
44 Oren, I. et al. (2006) Synaptic currents in anatomically identified CA3
neurons during hippocampal gamma oscillations in vitro. J. Neurosci.
26, 9923–9934
45 Brunel, N. and Wang, X.J. (2003) What determines the frequency of
fast network oscillations with irregular neural discharges? I. Synaptic
dynamics and excitation-inhibition balance. J. Neurophysiol. 90, 415–
430
46 Buhl, D.L. and Buzsaki, G. (2005) Developmental emergence of
hippocampal fast-field ‘ripple’ oscillations in the behaving rat pups.
Neuroscience 134, 1423–1430
47 Salinas, E. and Sejnowski, T.J. (2001) Correlated neuronal activity and
the flow of neural information. Nat. Rev. Neurosci. 2, 539–550
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Vol.30 No.7 349
48 Sanchez-Vives, M.V. and McCormick, D.A. (2000) Cellular and
network mechanisms of rhythmic recurrent activity in neocortex.
Nat. Neurosci. 3, 1027–1034
49 Engel, A.K. et al. (1991) Interhemispheric synchronization of
oscillatory neuronal responses in cat visual cortex. Science 252,
1177–1179
50 Kopell, N. et al. (2000) Gamma rhythms and beta rhythms have
different synchronization properties. Proc. Natl. Acad. Sci. U. S. A.
97, 1867–1872
51 Buzsaki, G. (2006) Rhythms of the Brain. Oxford University Press
52 Traub, R.D. et al. (1996) A mechanism for generation of long-range
synchronous fast oscillations in the cortex. Nature 383, 621–624
53 Sik, A. et al. (1994) Inhibitory CA1-CA3-hilar region feedback in the
hippocampus. Science 265, 1722–1724
54 Ceranik, K. et al. (1997) A novel type of GABAergic interneuron
connecting the input and the output regions of the hippocampus. J.
Neurosci. 17, 5380–5394
55 Buzsaki, G. et al. (2004) Interneuron Diversity series: Circuit
complexity and axon wiring economy of cortical interneurons.
Trends Neurosci. 27, 186–193
56 Buzsaki, G. and Draguhn, A. (2004) Neuronal oscillations in cortical
networks. Science 304, 1926–1929
57 Singer, W. (1993) Synchronization of cortical activity and its putative
role in information processing and learning. Annu. Rev. Physiol. 55,
349–374
58 Jensen, O. and Lisman, J.E. (2005) Hippocampal sequence-encoding
driven by a cortical multi-item working memory buffer. Trends
Neurosci. 28, 67–72
59 O’Keefe, J. and Recce, M.L. (1993) Phase relationship between
hippocampal place units and the EEG theta rhythm. Hippocampus
3, 317–330
60 Skaggs, W.E. et al. (1996) Theta phase precession in hippocampal
neuronal populations and the compression of temporal sequences.
Hippocampus 6, 149–172
61 Harris, K.D. et al. (2002) Spike train dynamics predicts theta-
related phase precession in hippocampal pyramidal cells. Nature
417, 738–741
62 Mehta, M.R. et al. (2002) Role of experience and oscillations in
transforming a rate code into a temporal code. Nature 417, 741–746
63 Huxter, J. et al. (2003) Independent rate and temporal coding in
hippocampal pyramidal cells. Nature 425, 828–832
64 Kamondi, A. et al. (1998) Theta oscillations in somata and dendrites of
hippocampal pyramidal cells in vivo: activity-dependent phase-
precession of action potentials. Hippocampus 8, 244–261
65 Lengyel, M. et al. (2005) Matching storage and recall: hippocampal
spike timing-dependent plasticity and phase response curves. Nat.
Neurosci. 8, 1677–1683
66 Hopfield, J.J. (1995) Pattern recognition computation using action
potential timing for stimulus representation. Nature 376, 33–36
67 Lisman, J.E. and Idiart, M.A. (1995) Storage of 7+/ 2 short-term
memories in oscillatory subcycles. Science 267, 1512–1515
68 Maurer, A.P. et al. (2006) Phase precession in hippocampal
interneurons showing strong functional coupling to individual
pyramidal cells. J. Neurosci. 26, 13485–13492
69 Ego-Stengel, V. and Wilson, M.A. (2007) Spatial selectivity and theta
phase precession in CA1 interneurons. Hippocampus 17, 161–174
70 Mann, E.O. and Paulsen, O. (2006) Keeping inhibition timely. Neuron
49, 8–9