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Physiology and Pharmacology of Striatal Neurons
Anatol C. Kreitzer
Gladstone Institute of Neurological Disease and Departments of Physiology and Neurology, University of California, San Francisco, California 94158; email:

Annu. Rev. Neurosci. 2009.32:127-147. Downloaded from by University of Manchester - John Rylands Library on 10/28/11. For personal use only.

Annu. Rev. Neurosci. 2009. 32:127–47 First published online as a Review in Advance on March 20, 2009 The Annual Review of Neuroscience is online at This article’s doi: 10.1146/annurev.neuro.051508.135422 Copyright c 2009 by Annual Reviews. All rights reserved 0147-006X/09/0721-0127$20.00

Key Words
basal ganglia, medium spiny neuron, interneuron, dopamine, acetylcholine

The basal ganglia occupy the core of the forebrain and consist of evolutionarily conserved motor nuclei that form recurrent circuits critical for motivation and motor planning. The striatum is the main input nucleus of the basal ganglia and a key neural substrate for procedural learning and memory. The vast majority of striatal neurons are spiny GABAergic projection neurons, which exhibit slow but temporally precise spiking in vivo. Contributing to this precision are several different types of interneurons that constitute only a small fraction of total neuron number but play a critical role in regulating striatal output. This review examines the cellular physiology and modulation of striatal neurons that give rise to their unique properties and function.


INTRODUCTION . . . . . . . . . . . . . . . . . . STRIATAL ANATOMY . . . . . . . . . . . . . . Compartments . . . . . . . . . . . . . . . . . . . . . Regions . . . . . . . . . . . . . . . . . . . . . . . . . . . STRIATAL NEUROMODULATORS . . . . . . . . . Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . Acetylcholine . . . . . . . . . . . . . . . . . . . . . . MEDIUM SPINY NEURONS . . . . . . . Membrane Properties . . . . . . . . . . . . . . Up and Down States . . . . . . . . . . . . . . . Neuromodulation . . . . . . . . . . . . . . . . . . INTERNEURONS . . . . . . . . . . . . . . . . . . Fast Spiking Interneurons . . . . . . . . . . Low-Threshold Spiking Interneurons. . . . . . . . . . . . . . . . . . . . Cholinergic Interneurons . . . . . . . . . . CONCLUSIONS . . . . . . . . . . . . . . . . . . . . 128 130 130 130 131 131 132 132 132 134 134 135 135 136 137 138

The striatum is a convergence point for glutamatergic inputs from cortex and thalamus, as well as dopaminergic afferents from the midbrain (Bolam et al. 2000, Kincaid et al. 1998, Smith et al. 1994). It is also the source of the direct and indirect pathways, two parallel basal ganglia circuits that are critical for motor function and procedural learning (Albin et al. 1989, DeLong 1990, Smith et al. 1998). The importance of the striatum for basal ganglia function is highlighted by neurological disorders in which striatal function is compromised (Graybiel 2000). In Parkinson’s disease, dopaminergic afferents to the striatum are lost and striatal output via the direct and indirect pathways is altered, resulting in impaired movement capabilities. In Huntington disease, striatal projection neurons become dysfunctional and degenerate, leading to a disconnection of the striatum from downstream basal ganglia nuclei and severe motor deficits (Albin et al. 1989, DeLong 1990). Striatal dysfunction is also implicated in other

MSN: medium spiny neuron SNr: substantia nigra pars reticulata GP: globus pallidus DA: dopamine ACh: acetylcholine

neurological disorders including dystonia, obsessive-compulsive disorder, and addiction (Breakefield et al. 2008, Graybiel 2008, Hyman et al. 2006). Thus, understanding striatal physiology is of paramount importance to deciphering basal ganglia function in health and disease. Striatal neurons (Figure 1a–d ) have been characterized at the anatomical, histochemical, and physiological levels (Kawaguchi et al. 1995, Wilson 1993). Anatomically, striatal cells fall into two main classes: (a) spiny projection neurons and (b) aspiny interneurons. Spiny projection neurons, also known as medium spiny neurons (MSNs), represent the vast majority of striatal neurons. They are GABAergic and can be classified into striatonigral (direct-pathway) and striatopallidal (indirect-pathway) subtypes on the basis of their axonal projections to the substantia nigra pars reticulata (SNr) or the globus pallidus (GP in rodents, external GP in primates) (Smith et al. 1998). MSNs receive glutamatergic inputs from cortex and thalamus that terminate predominantly on spines (Kemp & Powell 1971b). In addition, they are a main target of midbrain dopaminergic neuron axons that form synapses on MSN dendrites and spine necks (Smith et al. 1994). Histochemically, striatonigral MSNs express high levels of D1 and muscarinic M4 receptors, as well as dynorphin and substance P (Gerfen 1992, Ince et al. 1997). In contrast, striatopallidal MSNs are characterized by their high expression of dopamine D2 and adenosine A2A receptors, as well as their immunoreactivity for enkephalin (Gerfen 1992, Schiffmann et al. 1991). Physiologically, striatonigral and striatopallidal MSNs exhibit similar properties, although striatopallidal MSNs exhibit increased excitability (Kreitzer & Malenka 2007) and each type of MSN is differentially modulated by dopamine (DA) and acetylcholine (ACh) (Shen et al. 2007, Surmeier et al. 2007). Aspiny interneurons are far fewer in number and can be categorized anatomically into medium-sized GABAergic cells and large cholinergic cells (Kawaguchi et al. 1995). Medium-sized GABAergic interneurons can

Annu. Rev. Neurosci. 2009.32:127-147. Downloaded from by University of Manchester - John Rylands Library on 10/28/11. For personal use only.


(e) A coronal schematic of the mouse forebrain depicting the cortex and • Striatal Physiology and Pharmacology FS: fast spiking LTS: low-threshold spiking Bacterial artificial chromosome (BAC) transgenic mice: genetically engineered mice containing a gene of interest and surrounding genomic regulatory elements required for that gene’s cell-type specific expression pattern 129 . However. striatal interneurons are straightforward to identify electrophysiologically (Kawaguchi et al. and the dorsolateral. Finally. Vincent et al. these three classes of GABAergic interneurons display at least two different types of firing patterns (Kawaguchi et al. They also appear similar to MSNs under the light microscope. making them difficult to selectively target for recording. Rev. striatal interneurons receive glutamatergic afferents from cortex and thalamus. and ventral divisions of the striatum are schematically illustrated in the left hemisphere. detailed characterization of these neurons has proven difficult for several reasons. 2003). In the case of MSNs. 1995) but represent only a small fraction of total neuron number. (c) a low-threshold spiking interneuron (LTS). 1983). Drawings based on images from Kawaguchi (1993). Fortunately. it has been impossible to differentiate striatonigral and striatopallidal MSNs in vitro without post hoc analysis because of their similar anatomical and electrophysiological properties. they may also exhibit some characteristics of LTS interneurons (Tepper & Bolam 2004). Physiologically. forming microcircuits capable of modulating striatal output (Tepper et al. 1990). Although calretinin-positive interneurons have not been classified physiologically. 2004). (b) a fast spiking interneuron (FS). 1995. For personal use only. researchers have developed new technologies that enable the visualization of distinct striatal cell types for cellular and synaptic electrophysiology (Gong et al. Bacterial artifical chromosome (BAC) transgenic mice expressing green fluorescent protein in striatonigral or striatopallidal www. Somatostatinpositive interneurons have lower firing rates and plateau potentials and are known as low-threshold spiking (LTS) interneurons. Although investigators have known the basic physiological properties of striatal cell types for some time. Parvalbumin-positive neurons exhibit rapid and sustained firing rates in response to current injection and are alternatively known as fast spiking (FS) interneurons. be further classified histochemically into three subtypes: (a) parvalbumin-positive. (b) somatostatin-.a b MSN FS c Annu. and nitric oxide by University of Manchester . Schematic representations of (a) a striatal medium spiny neuron (MSN). 2009. Cowan et al. Like MSNs. and (d ) a cholinergic tonically active neuron (TAN). their output is directed primarily to MSNs and other interneurons. neuropeptide Y-. Tepper & Bolam 2004).John Rylands Library on 10/28/11. Chesselet & Graybiel 1986. 1990. Striatal patches ( pink) are illustrated in the right hemisphere. Neurosci. In contrast. and (c) calretinin-positive (Bennett & Bolam 1993. d LTS TAN Cortex 20 μm e Striatum Figure 1 Cell types and functional organization of the rodent striatum. dorsomedial. cholinergic interneurons can be physiologically characterized by their significant hyperpolarization-activated currents and spontaneous activity under physiological conditions (Wilson et al.annualreviews.32:127-147. Smith & Parent 1986. Downloaded from www.

1988). 2006. the dorsal striatum is divided by the internal capsule into the medially located caudate nucleus and the laterally positioned putamen. as are mouse lines labeling FS and LTS interneurons. the striatum exhibits a relatively uniform appearance. The ventral striatum—or nucleus accumbens—represents a third subdivision of the striatum. However. Ragsdale & Graybiel 1988). McGeorge & Faull 1989). suggesting a possible independent regulation of striatal output by DA in these compartments. Both striatopallidal and striatonigral MSNs are contained in the patch and matrix compartments (Gerfen & Young 1988). like the patches of the dorsal . Patches appear to receive innervation from a distinct set of ventral tier SNc neurons ( Jimenez-Castellanos & Graybiel 1987. making their connectivity similar to MSNs in ventral striatum (Gerfen 1985). This review focuses on the cellular physiology of different striatal neuron types. yielding no clear division between dorsomedial and dorsolateral striatum. whereas the axons of FS interneurons routinely cross compartment boundaries (Cowan et al. Fujiyama et al. Liles & Updyke 1985. Downloaded from www. These new tools have led to a resurgence in striatal research. 1986). Graybiel et al. Matrix MSNs receive inputs from cortex and thalamus (Donoghue & Herkenham 1986. and poor staining for cholinergic markers (Graybiel & Ragsdale 1978). including their membrane properties.32:127-147. whereas other markers label the matrix of neuropil surrounding these patches (Graybiel & Ragsdale 1978. firing patterns. also known as striosomes. The matrix compartment receives the bulk of sensorimotor striatal afferents and appears to be strongly regulated by both DA and ACh. The dense somatostatin and ChAT immunoreactivity in the matrix indicate that the axons of LTS and cholinergic interneurons may be preferentially localized to the matrix (Chesselet & Graybiel 1986. represent ∼10% of striatal volume and are distinguished by dense μ-opioid receptor binding (Herkenham & Pert 1981). Neurosci. Kincaid & Wilson 1996. 1992) and connect to both the SNr and the GP (Gerfen 1992). This patch/matrix organization (Figure 1e) is particularly important during development and segregates MSNs on the basis of their afferent and efferent projections (Gerfen 1992). 2009. However. 1972). although striatonigral MSNs in the patch compartment project to the substantia nigra pars compacta (SNc) rather than to the SNr (Gerfen 1984). Graybiel & Ragsdale 1978). Regions In primates.John Rylands Library on 10/28/11. Ragsdale & Graybiel 1981) and the dorsolateral striatum receives inputs from sensorimotor cortex (Kunzle 1975. Patches. the dorsomedial striatum receives inputs primarily from association cortices (Goldman & Nauta 1977. In rodents. Yin & Knowlton 2006).SNc: Substantia Nigra pars compacta ChAT: choline acetyltransferase MSNs are now readily available. it has long been noted that certain neurochemical markers label patches of striatum. Patch MSNs receive input primarily from limbic and frontal regions (Donoghue & Herkenham 1986.annualreviews. the matrix is defined by rich acetylcholinesterase and choline acetyltransferase (ChAT) staining (Graybiel et al. Olson et al. Prensa & Parent 2001). and modulation by DA and ACh. Parent & Hazrati 1995. substance P staining (Bolam et al. For personal use only. 1986. Rev. STRIATAL ANATOMY Annu. the two most prominent striatal neuromodulators. In contrast. McGeorge & Faull 1989. as well as immunoreactivity for calbinden (Gerfen et al. Sadikot et al. cholinergic neuromodulation is probably less prominent in these regions. Herkenham & Pert 1981. 1990). these striatal regions (Figure 1e) are anatomically and functionally distinct in both rodents and primates ( Joel & Weiner 1994. Compartments Under the light microscope. 1985) and somatostatin (Gerfen 1984). Given the apparent lack 130 Kreitzer of cholinergic markers in the by University of Manchester . The ventral striatum. descending motor axon bundles perforate the striatum. with distinct properties from both the dorsomedial and the dorsolateral striata (Nicola 2007).

For personal use only. 2009. Although some of these terminals are found directly adjacent to cortical synapses at spine necks (Freund et al. Midbrain DA neurons are spontaneously active at low frequencies (1–8 Hz) in vivo.18 μm (Arbuthnott & Wickens 2007). dopaminergic tone can be modulated on longer timescales in response to behavioral states including uncertainty. The axons of DA neurons arborize extensively in the striatal neuropil (Prensa & Parent 2001). The striatum is densely innervated by dopaminergic fibers originating in the SNc (dorsal striatum) and ventral tegmental area (ventral striatum). 1994). In response to behaviorally relevant stimuli (Schultz 2007a). striatal regions differ in several other important aspects. and striatal MSNs. www. These phasic spikes of DA are capable of activating lower-affinity Gs -coupled dopamine D1-type receptors (D1. However. Wu and Parent 2000). 2007). GABAergic interneurons. Consistent with this hypothesis. it is clear that DA reuptake mechanisms are not robust enough to limit spillover away from release sites. Schultz 2007b). most DA receptors are located extrasynaptically (Yung et al. 1995). most likely by activating high-affinity Gi coupled dopamine D2-type receptors (D2–D4) (Richfield et al. 1989). In addition. In addition to their connectivity. but not dorsomedial striatum (Herkenham et • Striatal Physiology and Pharmacology 131 Annu. giving rise to a dense matrix of en passant terminals capable of releasing DA over large regions of striatum. with higher densities in the medial striatum and the ventral striatum (Gerfen et al. Rev. This firing maintains a tonic DA tone that is critical for normal striatal function (Schultz 2007b). Nicola et al. In addition. cannabinoid CB1 receptors are highly expressed in ventral and dorsolateral striatum. STRIATAL NEUROMODULATORS Dopamine DA plays a fundamental role in normal basal ganglia function and movement (Heien & Wightman 2006.annualreviews. or reward (Schultz 2007a). dopaminergic neurons fire bursts of action potentials that briefly elevate striatal extracellular DA.annualreviews. a separate midbrain nucleus adjacent to the SNc (Fields et al. Dopaminergic boutons represent nearly 10% of all striatal synapses (Groves et al. D5) (Richfield et al. 1989). stress. whereas calbindin is highly expressed in dorsomedial striatum but only weakly expressed in dorsolateral striatum (Gerfen et al. . Smith et al. 1984. In contrast. Striatonigral and striatopallidal MSNs contain transcripts for both D1. in contrast to rodents (Wu & Parent 2000). 1994). 1985). Striatal region gene expression patterns also differ. DA receptors are present in every cell type in the striatum. 1990). primates have more calretinin-positive interneurons and also exhibit greater densities of parvalbumin-positive interneurons in the dorsomedial by University of Manchester . where they have been linked to modulation of dendritic conductances and synaptic integration (Nicola et al. Downloaded from www. with 10%–20% overlap of D1 and D2 receptor transcripts (Surmeier et al. 1993). Neurosci. 2000). receives glutamatergic inputs from frontal cortex and limbic regions (Brog et al.32:127-147. 2000. and shell regions are more similar to the amygdala (Zahm 2000). For example. and the nearest-neighbor distance between dopaminergic boutons is only ∼1. 1991). the dopaminergic innervation of the ventral striatum derives from the ventral tegmental area. including cell-type prevalence and gene expression patterns.and D2-class DA receptors.striatum. and cholinergic interneurons all express DA receptors. although different cell types express different DA receptor subtypes. 1985). 1985. The ventral striatum can be further subdivided into core and shell regions: Core regions display similarity to the dorsal striatum. Parvalbumin-positive (FS) interneurons are enriched in the lateral striatum and are much less evident in the medial striatum (Kita et al. somatostatin-positive (LTS) interneurons have a complementary distribution. suggesting that DA acts to some degree via volume transmission (Cragg & Rice 2004). Differences in regional density and prevalence are species specific: Primates exhibit a higher density of interneurons than do rodents (Graveland et al.John Rylands Library on 10/28/11.

2001). implying significant posttranscriptional control of DA receptor expression in MSNs. which are expressed widely 132 Kreitzer in the nervous system. but they can be classified into at least two types on the basis of their axonal projection patterns (Smith et al. acetylcholinesterase. In vivo. 2009. suggesting that this pause in cholinergic interneuron firing may be associated with behaviorally significant cues. Zhou et al. In contrast. 1997. mAChRs are expressed widely on MSNs.John Rylands Library on 10/28/11. nicotinic receptors are expressed mainly in presynaptic DA terminals and FS interneurons (Koos & Tepper 2002. cholinergic interneurons exhibit tonic low-frequency activity (<10 Hz) that is transiently inhibited in response to visual or auditory cues associated with movement tasks (Aosaki et al. Rivera et al.32:127-147. Weiner et al. striatopallidal MSNs send axons to the GP. and GABAergic interneurons. All MSNs share a similar morphology. 2002). 1998). 2002). Yan & Surmeier 1997). particularly in presynaptic terminals where they can enhance neurotransmitter release (Zhou et al. 1994a. 2004). 1984. Rev. Matsumoto et al. 1990). Yan et al. Immunohistochemical and functional evidence indicates that striatal GABAergic interneurons express primarily D5 receptors (Centonze et al. 2001). M1. 1996). as well. MEDIUM SPINY NEURONS Membrane Properties The principal neurons of the striatum are the MSNs. M1 receptors are expressed in all MSNs. Zhou et al. although there is some evidence for expression on glutamatergic terminals. Although cholinergic interneurons constitute less than 1% of all striatal neurons (Rymar et al. However. Kimura 1986). All five muscarinic receptor subtypes (M1–M5) are expressed in the dorsal striatum. by University of Manchester . 1992. 1997. This class of afferents project . The pause appears to require coordinated synaptic inputs from both the SNc and intralaminar thalamic nuclei (Aosaki et al. Apicella et al. The extent of D3–D5 receptor expression in MSNs remains unclear. Striatopallidal MSNs appear to receive a bulk of the sensorimotor corticostriatal afferents (Berretta et al. Nicotinic receptors are pentameric ligandgated ion channels. However. 1991. Annu. which may serve to limit ACh diffusion. 2000. ACh is rapidly degraded by an efficient extracellular enzyme. their dense and extensive axonal arborization ensures widespread release of ACh. ACh acts at both nicotinic (nAChR) and muscarinic (mAChR) receptors in the striatum. thus only indirectly connecting to basal ganglia output nuclei through a polysynaptic pathway. although the precise mechanisms have yet to be determined (Bennett & Wilson 1998). 2004). Schwartz et al. cholinergic interneurons.annualreviews. Yan & Surmeier 1996). In contrast. which is released into the extracellular space by tonically active cholinergic interneurons (Bolam et al. Neurosci. Striatonigral MSNs project directly to basal ganglia output nuclei: internal globus pallidus (primates)/entopeduncular nucleus (rodents) and the SNr. whereas cholinergic interneurons express both D2 and D5 receptors (Yan et al. In contrast. Parthasarathy & Graybiel 1997). In the striatum. M2 receptors are found exclusively in cholinergic interneurons (Bernard et al. Rymar et al. immunohistochemical studies indicate only a 1% overlap between D1 and D2 (Ince et al. 1995.1996). whereas M4 receptors are restricted to direct-pathway MSNs (Ince et al. 2002). which represent >95% of all striatal neurons and form the sole output to downstream basal ganglia nuclei (Kemp & Powell 1971a. 1990). 2001. For personal use only. which like DA may act locally on MSN synapses (Izzo & Bolam 1988) and have a more widespread influence via volume transmission (Contant et al. 1997. Downloaded from www. 2003a. and M5 receptors are Gq -coupled. where—along with M4 receptors—they function as cholinergic autoreceptors regulating ACh release (Alcantara et al. whereas M2 and M4 receptors are Gi -coupled. 1984. 1997). 2002). Acetylcholine ACh represents a second major striatal neuromodulator (Calabresi et al. Wilson et al.

topographically from cortex to the striatum. Neurosci. which can activate both small. Surmeier et al. Nisenbaum et al. 2004). as well as by several types of potassium conductances that shape their characteristic firing patterns (Nisenbaum & Wilson 1995) (Figure 2a). and a long delay to initial spiking. Shen et al. 1989). c LTS d TAN Figure 2 Firing properties of striatal neurons. 1996. www. Tkatch et al. LTS interneurons (c) have high input resistance and a sustained plateau potential that persists after the end of current injections. 1996. 1998.32:127-147. which together yield a slow depolarization and delay to the initial spike (Nisenbaum et al. 1991. 1998). 1999) and limit MSN firing rates. they do share a number of physiological properties. Rev. 1984). Tonically active cholinergic interneurons (TANs) (d ) exhibit a prominent hyperpolarization-activated current and broad spikes with long spike afterhyperpolarizations. and rapid membrane time constants (Mermelstein et al. At rest. and a vast majority of studies have considered them as a single cell type. Additionally. low input resistance. inward rectification. a reduction in available Kirs in a 20 mV 100 ms MSN b FS Annu. 2000). An early hint that MSN subtypes might exhibit different physiological properties came from studies of Kirs in striatopallidal and striatonigral MSNs of the nucleus accumbens (Mermelstein et al. both classes of MSNs receive synapses from interneurons as well as axon collaterals from other MSNs (Tepper et al. 2009. Uchimura et al. Downloaded from www. FS interneurons (b) have low input resistance and a characteristic rapid firing pattern. projections from neighboring barrels in mouse somatosensory cortex are targeted to discrete neighboring regions of striatal neuropil (Wright et al.2) A-type potassium currents. Given the hyperpolarized resting potential of typical MSNs.(Kv4.2) and slowinactivating (Kv1. 2005. Whole-cell current-clamp recordings were performed from different striatal cell types. Membrane depolarization inactivates Kirs and activates both fast. inwardly rectifying potassium channels (Kirs) contribute to their negative resting • Striatal Physiology and Pharmacology 133 . MSNs are characterized by their hyperpolarized resting membrane potential and low input resistance (Kita et al. For personal use only.annualreviews.and large-conductance calcium-activated potassium channels (Bargas et al. MSNs (a) exhibit low input resistance. By using post hoc reverse-transcriptase polymerase chain reaction (RT-PCR) analysis to identify MSN subtypes. for example. Although MSNs do not represent a homogenous population. 1989. 1999). 2004.John Rylands Library on 10/28/11. Depolarization and spiking also yield calcium influx. LTS interneurons also display rebound spiking following hyperpolarizations (not shown here). striatopallidal MSNs were found to exhibit Kir currents that inactivated more readily at hyperpolarized by University of Manchester .annualreviews. as well as a persistent potassium conductance (Kv7).

Up and Down states in MSNs arise from the intrinsic membrane properties of MSNs as well as from the nature and coherence of excitatory synaptic drive from cortex and thalamus (Wilson & Kawaguchi 1996). which are activated in the Up state (Carter & Sabatini 2004) and are required for the induction of striatal long-term depression (Choi & Lovinger 1997. However. Activation of D1 receptors reduces sodium currents (Schiffmann et al. In addition to differences in Kir inactivation properties. Spiking was observed only during Up states. Up and Down States Early in vivo studies of striatal MSNs noted irregular rhythmic firing patterns that were accompanied by membrane potential shifts from hyperpolarized potentials (−90 to −70 mV) to more depolarized potentials (−60 to −40 mV) (Wilson & Groves 1981). Up states correlated among striatal MSNs. Kir properties in striatopallidal MSNs contribute to their increased excitability. Calcium-permeable AMPA receptors: GluR2-lacking receptors that exhibit calcium permeability and strong inward rectification that arises from block by intracellular polyamines at depolarized potentials striatopallidal MSNs could significantly increase their excitability. and even quiescent MSNs exhibited subthreshold membrane potential fluctuations. if sufficient numbers of glutamatergic inputs become active. Striatonigral MSNs express D1 receptors. For personal use only. Downloaded from www. Recent work indicates that Up and Down states are most prominent under anesthesia and during slow-wave sleep. 1995. Additionally.annualreviews. which were subsequently termed Down and Up states. Surmeier et al. although still present. and calcium channels. Rev. 2009. However. Neurosci. State transitions. The stability of MSNs at rest (Down state) is due to high levels of Kir that limit membrane depolarization in response to excitatory synaptic inputs. a more recent study using BAC transgenic mice found that striatopallidal MSNs fired at higher rates in response to current injections (Kreitzer & Malenka 2007). MSNs can be depolarized Kreitzer enough to block Kirs. are less obvious under these conditions (Mahon et al. At depolarized Up state potentials. although excitability differences persist even during large current injections that significantly depolarize MSNs and should block Kirs (Kreitzer & Malenka 2007). suggesting that other factors may be important. excitatory postsynaptic potentials are mediated almost entirely by AMPA receptors. MSNs express low-voltageactivated l-type calcium channels (Cav1. Neuromodulation Striatal MSNs exhibit numerous ionic conductances that shape their firing properties. 1992) and enhances Kirs (Pacheco-Cano et al. NMDA receptors are also activated. D1 receptors also enhance l-type currents that are activated in the Up state (Carter & Sabatini 2004. 1996). both of which are predicted to reduce MSN excitability. 2007). shifting MSNs into the Up state (Blackwell et al. In contrast. Kreitzer & Malenka 2005). 1998).John Rylands Library on 10/28/11.3). The Up state persists as long as sufficient excitatory drive is present to maintain depolarization. potassium. but blocked by intracellular polyamines at depolarized potentials Annu. 2006). Up state transitions also change the properties of synaptic conductances. Thus. consistent with the hypothesis that MSNs receive converging inputs from cortical neurons that fire in a correlated—but not totally synchronous—manner. which regulate sodium. The magnitude of the Up state shift is determined by voltage-sensitive potassium conductances that become activated following depolarization and serve to limit the extent of synaptically driven depolarization (Wilson & Kawaguchi 1996).org by University of Manchester . yielding slower excitatory potentials that summate more readily. 134 . although not every Up state yielded a spike. and many of these conductances are sensitive to neuromodulators such as DA and ACh.32:127-147.Inwardly rectifying potassium channels: a voltage-sensitive potassium channel that is permeable to potassium at hyperpolarized potentials. 2003). striatopallidal Kirs also display relatively greater inhibition by muscarinic M1 receptors than do striatonigral neurons (see below for further discussion) (Shen et al. although individual spikes did not (Stern et al. In the Down state. Up state transitions also shift the dominant source of synaptic calcium influx from calcium-permeable AMPA receptors to NMDA receptors (Carter & Sabatini 2004). the waking state is characterized by noisy MSN membrane fluctuations. Consistent with this finding.

yet they are critical for regulating striatal output. Downloaded from www. which is particularly sensitive to PIP2 depletion (Du et al. like D1 receptors. Further studies will be required to clarify this issue. which should facilitate Up state transitions. which are expressed by striatopallidal and striatonigral MSNs. although their particular role has been disputed. Rymar et al. INTERNEURONS Fast Spiking Interneurons FS interneurons represent only a few percent of all striatal neurons (Kita et al.32:127-147. D2 receptors may reduce the excitatory drive necessary for Up state transitions on a timescale of seconds. 1990). D1 receptors facilitate the firing of striatonigral MSNs. 2007).John Rylands Library on 10/28/11. if excitatory synaptic drive Annu. Yin & Lovinger 2006). It is intriguing to note that D2 receptors. M1 activation in striatal MSNs also facilitated depolarization-evoked endocannabinoid release (Narushima et al.3 expression. M1 activation also blocks a persistent potassium current mediated by Kv7 channels (Shen et al. Moreover. In contrast. leading to enhanced spiking. A-type potassium currents are partially activated. inhibit www. In the hippocampus and cerebellum. these findings suggest that D1 receptor activation acts as a filter to limit Up state transitions to periods of significant excitatory drive. these findings indicate that M1 activation increases MSN excitability and also enhances the likelihood of state transitions in striatopallidal MSNs. This modulation is selective for striatopallidal MSNs because of their high level of Kir2. Striatopallidal MSNs exhibit high levels of D2 receptor expression and prominently express a form of endocannabinoid-dependent long-term depression of glutamatergic synapses (Kreitzer & Malenka 2007). 1998). 1999. Neurosci. once in the Up state. 2005). However. M1 activation inhibits N. 2007). they also inhibit l-type currents and reduce spiking in the Up state (Hernandez-Lopez et al. 2009.and P/Qtype calcium channels that couple to calciumactivated potassium channels in MSNs. 1995).org by University of Manchester . which should also enhance firing in the Up state (Nisenbaum et al. mainly inhibit MSN firing. giving rise to an enhancement of firing when neurons are depolarized (Hernandez-Lopez et al. which will tend to keep MSNs hyperpolarized. M1 receptors have also been linked to endocannabinoid production in MSNs. Thus. Cholinergic modulation of MSNs is mediated by muscarinic ACh receptors (Yan et al. activation of Gq coupled receptors such as M1/3 or mGluR1/5 stimulates endocannabinoid production via phospholipase Cβ. 2004). Rev. which represent a class of lipophilic membrane-derived signaling molecules produced in neurons in response to elevations of intracellular calcium and PLC activation (Piomelli 2003). However. Mice with decreased numbers of striatal FS neurons exhibit procedural learning deficits (Marrone et al. 2006). Furthermore. Thus. For personal use only. Activation of M1 receptors. D2 receptors. when MSNs are in the Down state. shifts the activation and inactivation of transient A-type potassium currents to more hyperpolarized potentials (Akins et al. D1 receptors block a slowly inactivating potassium conductance. • Striatal Physiology and Pharmacology 135 .annualreviews. while increasing the requirement for synchrony on the milliseconds timescale to drive spiking. 2006). Although they reduce Kir currents (Uchimura & North 1990). 2004). 1990. exhibit opposite effects in the Down and Up states. which are expressed at high levels in striatopallidal MSNs. 1997). M1 receptor activation inhibits Kirs via phospholipase C activation and depletion of phosphatidylinositol biphosphate (PIP2 ) (Shen et al. a different study concluded that M1 receptor activation might actually inhibit endocannabinoid release via inhibition of l-type voltage-sensitive calcium channels in MSNs (Wang et al. Striatal D2 receptors have also been linked to mobilization of endocannabinoids (Giuffrida et al. However. 2005).annualreviews. however. 2001).Surmeier et al. 2000). can overcome these currents and shift MSNs into the Up state. then these A-type potassium currents will also inactivate more readily and reduce delays to spiking. Together. and injections of GABAA antagonists into the putamen increase MSN firing (Mallet et al.

which receive small numbers of inputs from large numbers of afferents. In vivo. FS interneurons exhibit higher firing frequencies than do MSNs and may entrain oscillations between cortex and striatum (Berke et al. even bursts in single interneurons can significantly delay spiking in MSNs (Koos & Tepper 1999). LTS interneurons represent a few percent of striatal neurons (Rymar et al. Kubota et al. LTS interneurons are innervated by glutamatergic afferents from both cortex and thalamus. 1998). FS interneurons have faster response latencies than do MSNs in vivo and may limit the duration of MSN spiking. and nitric oxide synthase (Chesselet & Graybiel 1986. Unlike MSNs. 2005) owing to both a reduced excitatory drive on MSNs and an increased inhibitory tone. Thus. Thus. where they form numerous proximal synapses capable of inhibiting the generation of action potentials in MSNs (Bennett & Bolam 1994. 1995). They are relatively enriched in dorsolateral striatum (Bennett & Bolam 1994. Koos & Tepper 1999). ACh also excites FS interneurons through a direct depolarization mediated by nondesensitizing nicotinic receptors. 1989).32:127-147. Striatal FS interneurons share properties similar to FS interneurons in the hippocampus and cortex. 1991). Vuillet et al. Given the prominent role of FS interneurons in regulating MSN spiking. Koos & Tepper 1999. 2004). For personal use only. Kita et al. 1990) (Figure 2b). FS interneurons display dendritic gap junctions and exhibit electrotonic coupling (Kita et al. ACh may also indirectly facilitate FS firing by enhancing DA release via presynaptic nicotinic receptors (Zhou et al. However. Vuillet et al. 2002) and thalamus (Sidibe & Smith 1999) and receive inhibitory inputs from other interneurons (Chang & Kita 1992) and a population of globus pallidus neurons (Bevan et by University of Manchester . 1999). Low-Threshold Spiking Interneurons A second type of GABAergic striatal interneuron is the LTS cell. Ramanathan et al. Lapper et al. elevations in ACh are predicted to excite FS interneurons directly. and induce dystonia (Yamada et al. and in turn form synapses onto MSNs (Sidibe & Smith 1999. FS interneurons often receive multiple synaptic contacts from individual afferent fibers (Ramanathan et al. they do not require the same degree of input synchrony that MSNs need to trigger a spike. 1990. Neurosci. Kita et al. 136 Kreitzer Annu. This influence arises from the presence of multiple synaptic contacts on MSNs. 2005). Mallet et al. Kita 1993. 2003b) and also via D2-mediated inhibition of GABAergic afferents onto FS interneurons (Bracci et al. modulation of their firing properties by neuromodulators should be important for striatal function. elevated DA would directly excite FS interneurons but simultaneously inhibit cholinergic interneurons (see below). which can lead to firing synchrony among local interneuron populations. such as short-duration spikes. Centonze et al. neuropeptide Y. DA excites FS interneurons via D5 receptor activation (Bracci et al. FS interneurons receive excitatory synapses from both cortex (Kita 1993. 2004) and exhibit fewer dendritic branches. Smith & Parent 1986. FS interneurons mainly target MSNs. In addition. 2002). as well as less dense and more extensive axonal arborizations relative to FS interneurons (Kawaguchi 1993.John Rylands Library on 10/28/11. MSN synapses onto interneurons were not observed. 1995. which could mitigate DA-mediated FS excitation to some degree.spiking in the SNr (Yamada et al. 2009. high-frequency firing. and gap junctions with other FS interneurons (Kawaguchi 1993. 2002). suggesting that they play a key role in sensorimotor integration. whereas a single interneuron connects to 135–541 MSNs (Koos & Tepper 1999). 1990). . 2002. as well as from their proximal location on MSN somata and dendrites (Kubota & Kawaguchi 2000). 1992. Desynchronized cortical activity enhances interneuron spiking and leads to a dramatic reduction in MSN spiking activity (Mallet et al. Researchers estimate that a single MSN receives inhibitory synapses from 4–27 FS interneurons. Rev. Like FS interneurons. 2002). which likely plays a role in the induction of striatal long-term plasticity (Calabresi et al.annualreviews. Downloaded from www. 1983). Vincent et al. 1993. Yoshida et al. In contrast. LTS interneurons express somatostatin.

1994.Annu. Thus. but also on FS interneurons (Chang & Kita 1992. 1998). leading to significant increases in spiking (Centonze et al. Wilson et al. Modulation of striatal interneurons has not been well characterized. constitute only 1%–2% of striatal cells (Kemp & Powell 1971a). A characteristic feature of cholinergic interneurons in vivo is their pause in tonic firing in response to salient cues.annualreviews. which have not been well characterized (Bennett & Bolam 1993. Cholinergic interneurons receive only sparse excitatory innervation. M2 receptors may also function as presynaptic autoreceptors (Hersch et al. 2004). Cholinergic interneurons fire spontaneously in vivo owing to their expression of sodium currents and hyperpolarization-activated cation currents (Bennett et al. Neurosci. 1993. Muscarinic M1 and M2 receptors are also expressed in LTS interneurons (Ariano & Kenny 1989. and these serve to amplify and prolong the effects of hyperpolarizing inputs (Wilson 2005). Kubota et al. Electrophysiologically. Muscarinic M2 and M4 receptors. express Kirs that become unblocked at hyperpolarized potentials. 1994a.32:127-147. the cortex (Thomas et al. 2002). as well as M2 and M4 mAChRs (Bergson et al. A second population of LTS interneurons may correspond to calretininpositive interneurons. but their physiological roles remain unknown. Activation of these receptors depolarizes LTS interneurons. D1-type and D2-type dopamine receptors exert opposite effects on excitability within individual cholinergic interneurons. Wilson & Goldberg 2006).John Rylands Library on 10/28/11. 1994b. Cholinergic Interneurons Cholinergic interneurons. 1998). in addition. 1984. Levey et al. Phelps et al. They also receive inhibitory synapses from MSNs (Bolam et al. but their influence is significant. which form synapses primarily on MSNs (Bolam et al. D5 receptor activation depolarizes cholinergic interneurons through a cAMP-dependent mechanism (Aosaki et al. including reward and reward prediction (Aosaki et al. Hersch et al. 1994) regulating ACh release via direct Gβ/γ-mediated inhibition of presynaptic calcium channels (Yan & Surmeier 1996). 1995. 2009. 2004). these interneurons display higher input resistances and relatively depolarized resting potentials (Kawaguchi 1993) (Figure 2c). whereas D2 signaling mediates an inhibition of voltage-sensitive sodium channels that reduces excitability (Maurice et al. 1990. LTS interneurons are characterized by their plateau potentials and low-threshold spikes. 1993). Cholinergic interneurons. reduce excitability albeit through a different mechanism involving activation of a potassium conductance (Calabresi et al. They have large (20–50 μm diameter) cell bodies and widespread axonal fields. Bernard et al. like other striatal interneurons. express D5 receptors (Rivera et al. 2002). 2000). However. The instrinsic properties of cholinergic interneurons are also critical. Downloaded from www. LTS interneurons. 1998).org • Striatal Physiology and Pharmacology 137 . Morris et al. 1985). Graybiel et al. like MSNs. 1989). Rev. although the precise signaling mechanisms are not clear. www. Cholinergic interneurons express both D2 and D5 receptors. Although the precise origins of this pause are still unclear. 2000). Koos & Tepper 2002). although their innervation by dopaminergic axons is prominent in both dorsal and ventral striata. 2001). which derives primarily from the thalamus (Lapper & Bolam 1992) and. For personal use only. 1988). 1992. also known as large aspiny neurons or tonically active neurons. to a lesser extent. Cholinergic interneurons can be electrophysiologically distinguished by their depolarized resting potential and highinput resistance (Kawaguchi 1993) (Figure 2d ).org by University of Manchester . Tepper & Bolam 2004) but appear to lack significant thalamic innervation (Sidibe & Smith 1999). 1994. like D2 receptors. Izzo & Bolam 1988. some LTS interneurons also appear to receive significant dopaminergic innervation (Hidaka & Totterdell 2001. owing primarily to calcium-activated potassium channels (Kawaguchi 1992. Matsumoto et al.annualreviews. 1986). Their firing rates are limited to 2–10 Hz by a prominent afterhyperpolarization following each spike. it requires both intact thalamic and dopaminergic innervation to occur (Aosaki et al.

138 Kreitzer reduced autoinhibition of ACh release might compensate to some extent for this reduction in cholinergic tone. Rev. given its relatively higher affinity for DA (Richfield et al. FS and LTS interneurons are depicted in blue and red. In addition to differences in synaptic convergence. Schematic depicting different types of striatal neurons and their complement of dopamine and acetylcholine receptors. as well as on DA and ACh release itself. 2009. and subsequent reductions in cholinergic tone. Similarly. Neurosci.annualreviews. increased dopaminergic tone is predicted to increase D2 receptor activation selectively. Excitability of both FS and LTS interneurons would be increased. respectively.nAChR D5 s D2 i D1 M1 q M1 q s i M4 FS Indirect MSN Direct MSN D5 M4 M2 i D2 i i D5 s Annu. changes in ACh or DA levels will exert complex effects on striatal neuron activity. For example. and the cholinergic neuron is shown in green. G protein–coupled receptors are displayed with their associated G-protein: Gs (magenta). Reduced depolarization of FS interneurons via nicotinic receptors would also occur. For personal use only.32:127-147. Downloaded from www. intrinsic membrane properties. Thus. FS interneurons also express the ionotropic nicotinic ACh receptor. whereas striatopallidal MSNs would be inhibited. Large increases in DA yield both D1 and D2 receptor activation. However. brief spikes in DA concentrations could exert significantly different effects. reduced activation of presynaptic nicotinic receptors on dopamine terminals would reduce DA release itself. Gi ( purple). 1989). decreased cholinergic interneuron activity. and in vivo firing patterns.John Rylands Library on 10/28/ by University of Manchester . CONCLUSIONS Significant heterogeneity exists within both interneuron and projection neuron populations in the striatum. This would lead to decreased striatopallidal MSN output. In contrast. rendering them less excitable. each type of striatal neuron expresses a distinct complement of DA and ACh receptors (Figure 3). yielding more powerful feedforward inhibition and increased temporal precision of MSN . striatonigral MSN output would be enhanced. Striatopallidal (indirect-pathway) and striatonigral (direct-pathway) MSNs are shown in gray. M1 q s i M2 LTS TAN Figure 3 Dopaminergic and cholinergic modulation of striatal neurons. Thus. and the system would reestablish an equilibrium level of DA and ACh. or Gq (blue).

annualreviews. Given the diversity of striatal neurons and their responses to various neuromodulators. 2006). Penney JB. whereas neighboring striatonigral MSNs retain normal morphology (Day et al. Muscarinic modulation of a transient K+ conductance in rat neostriatal neurons. 1998. J. 12:366–75 Alcantara AA. Dopamine D1-like receptor activation excites rat striatal large aspiny neurons in vitro.Annu. DISCLOSURE STATEMENT The author is not aware of any affiliations. striatal interneurons are selectively spared (Cicchetti et al. nitric oxide. Future studies will be required to understand how these various factors interact to regulate basal ganglia circuit function. Neurosci. striatopallidal MSNs are selectively vulnerable to cell death (Mitchell et al. Our research on this subject is supported by the Pew Charitable Trusts.annualreviews. 434:445–60 Aosaki T. memberships. Neurol. and The J. 1990. 2001. At the same time. 1995. David Gladstone Institutes. Kitai ST. Science 265:412–15 Aosaki T. Interestingly. Trends Neurosci. the physiological properties of striatal neurons also depend on the properties of their synaptic inputs. 1985). Kiuchi K. 73:1234–52 Aosaki T. J. and various neuropeptides play important roles in shaping the physiology of striatal neurons. The functional anatomy of basal ganglia disorders. Surmeier DJ. striatopallidal MSNs exhibit increased firing rates (Mallet et al. Effect of the nigrostriatal dopamine system on acquired neural responses in the striatum of behaving monkeys. Neurosci. 1999. ACKNOWLEDGMENTS I thank members of my laboratory for their critical reading of the manuscript and Carlo Tringale for administrative assistance. Mrzljak L. In addition. 1994a. However. 1989. J. Young AB. LITERATURE CITED Akins PT. a host of other neuromodulators including adenosine. Kimura M. although both types of MSNs eventually degenerate. the CHDI Foundation. spiking output. Comp. The increased prevalence of interneurons in Huntington disease could exacerbate striatal deficits arising from loss of MSNs (Cepeda et al. endocannabinoids. Kawaguchi Y. 2006). Hersch SM. 2009. Neurophysiol. Temporal and spatial characteristics of tonically active neurons of the primate’s striatum. Graybiel • Striatal Physiology and Pharmacology 139 . funding. Ferrante et al. which suggests that this decrease in spine density may reflect a compensatory mechanism aimed at reducing overexcitation. Rev. 1996. Reiner et al. Kimura M.32:127-147.John Rylands Library on 10/28/11. Graybiel AM. Heterogeneity among neuronal populations is therefore a critical factor to consider when studying striatal function. 18:5180–90 www. Downloaded from www. In contrast. Recent evidence indicates that striatopallidal MSNs undergo spine loss following dopamine depletion. it is also apparent that significant caution is required in experimental design and data interpretation when performing pharmacological manipulations in the intact striatum. For personal use only. In Huntington by University of Manchester . Cholinergic interneurons would exhibit more complex changes owing to the opposing actions of simultaneous D2 and D5 receptor activation. Muscarinic m1 and m2 receptor proteins in local circuit and projection neurons of the primate striatum: anatomical evidence for cholinergic modulation of glutamatergic prefronto-striatal pathways. 1988). diseases of the striatum such as Parkinson disease and Huntington disease selectively affect particular neuronal subtypes. Jakab RL. or financial holdings that might be perceived as affecting the objectivity of this review. 2004). Levey AI. Goldman-Rakic PS. Nature 344:240–42 Albin RL.

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