Kreitzer Physiology and Pharmacology of Striatal Neurons

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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: akreitzer@gladstone.ucsf.edu
Annu. Rev. Neurosci. 2009.32:127-147. Downloaded from www.annualreviews.org by University of Manchester - John Rylands Library on 10/28/11. For personal use only.
Annu. Rev. Neurosci. 2009. 32:12747 First published online as a Review in Advance on March 20, 2009 The Annual Review of Neuroscience is online at neuro.annualreviews.org This articles 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
Abstract
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.
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Contents
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
INTRODUCTION
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 Parkinsons 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 decits (Albin et al. 1989, DeLong 1990). Striatal dysfunction is also implicated in other
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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 (Breakeeld 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 1ad ) 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 classied 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
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MSN
FS
c
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TAN
Cortex
20 m
Striatum
Figure 1 Cell types and functional organization of the rodent striatum. Schematic representations of (a) a striatal medium spiny neuron (MSN), (b) a fast spiking interneuron (FS), (c) a low-threshold spiking interneuron (LTS), and (d ) a cholinergic tonically active neuron (TAN). Drawings based on images from Kawaguchi (1993). (e) A coronal schematic of the mouse forebrain depicting the cortex and striatum. Striatal patches ( pink) are illustrated in the right hemisphere, and the dorsolateral, dorsomedial, and ventral divisions of the striatum are schematically illustrated in the left hemisphere.
be further classied histochemically into three subtypes: (a) parvalbumin-positive; (b) somatostatin-, neuropeptide Y-, and nitric oxide synthase-positive; and (c) calretinin-positive (Bennett & Bolam 1993, Chesselet & Graybiel
1986, Cowan et al. 1990, Smith & Parent 1986, Vincent et al. 1983). Physiologically, these three classes of GABAergic interneurons display at least two different types of ring patterns (Kawaguchi et al. 1995, Tepper & Bolam 2004). Parvalbumin-positive neurons exhibit rapid and sustained ring rates in response to current injection and are alternatively known as fast spiking (FS) interneurons. Somatostatinpositive interneurons have lower ring rates and plateau potentials and are known as low-threshold spiking (LTS) interneurons. Although calretinin-positive interneurons have not been classied physiologically, they may also exhibit some characteristics of LTS interneurons (Tepper & Bolam 2004). Finally, cholinergic interneurons can be physiologically characterized by their signicant hyperpolarization-activated currents and spontaneous activity under physiological conditions (Wilson et al. 1990). Like MSNs, striatal interneurons receive glutamatergic afferents from cortex and thalamus. However, their output is directed primarily to MSNs and other interneurons, forming microcircuits capable of modulating striatal output (Tepper et al. 2004). Although investigators have known the basic physiological properties of striatal cell types for some time, detailed characterization of these neurons has proven difcult for several reasons. In the case of MSNs, it has been impossible to differentiate striatonigral and striatopallidal MSNs in vitro without post hoc analysis because of their similar anatomical and electrophysiological properties. In contrast, striatal interneurons are straightforward to identify electrophysiologically (Kawaguchi et al. 1995) but represent only a small fraction of total neuron number. They also appear similar to MSNs under the light microscope, making them difcult to selectively target for recording. Fortunately, researchers have developed new technologies that enable the visualization of distinct striatal cell types for cellular and synaptic electrophysiology (Gong et al. 2003). Bacterial artical chromosome (BAC) transgenic mice expressing green uorescent protein in striatonigral or striatopallidal
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FS: fast spiking LTS: low-threshold spiking Bacterial articial chromosome (BAC) transgenic mice: genetically engineered mice containing a gene of interest and surrounding genomic regulatory elements required for that genes cell-type specic expression pattern
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SNc: Substantia Nigra pars compacta ChAT: choline acetyltransferase
MSNs are now readily available, as are mouse lines labeling FS and LTS interneurons. These new tools have led to a resurgence in striatal research. This review focuses on the cellular physiology of different striatal neuron types, including their membrane properties, ring patterns, and modulation by DA and ACh, the two most prominent striatal neuromodulators.
STRIATAL ANATOMY
Compartments
Under the light microscope, the striatum exhibits a relatively uniform appearance. However, it has long been noted that certain neurochemical markers label patches of striatum, whereas other markers label the matrix of neuropil surrounding these patches (Graybiel & Ragsdale 1978, Herkenham & Pert 1981, Olson et al. 1972). 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). Both striatopallidal and striatonigral MSNs are contained in the patch and matrix compartments (Gerfen & Young 1988), although striatonigral MSNs in the patch compartment project to the substantia nigra pars compacta (SNc) rather than to the SNr (Gerfen 1984). Patches, also known as striosomes, represent 10% of striatal volume and are distinguished by dense -opioid receptor binding (Herkenham & Pert 1981), substance P staining (Bolam et al. 1988), and poor staining for cholinergic markers (Graybiel & Ragsdale 1978). Patch MSNs receive input primarily from limbic and frontal regions (Donoghue & Herkenham 1986, Kincaid & Wilson 1996, Ragsdale & Graybiel 1988), making their connectivity similar to MSNs in ventral striatum (Gerfen 1985). Patches appear to receive innervation from a distinct set of ventral tier SNc neurons ( Jimenez-Castellanos & Graybiel 1987, Prensa & Parent 2001), suggesting a possible independent regulation of striatal output by DA in these compartments. Given the apparent lack
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of cholinergic markers in the patch, cholinergic neuromodulation is probably less prominent in these regions. In contrast, the matrix is dened by rich acetylcholinesterase and choline acetyltransferase (ChAT) staining (Graybiel et al. 1986, Graybiel & Ragsdale 1978), as well as immunoreactivity for calbinden (Gerfen et al. 1985) and somatostatin (Gerfen 1984). Matrix MSNs receive inputs from cortex and thalamus (Donoghue & Herkenham 1986, Fujiyama et al. 2006, Sadikot et al. 1992) and connect to both the SNr and the GP (Gerfen 1992). 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, Graybiel et al. 1986), whereas the axons of FS interneurons routinely cross compartment boundaries (Cowan et al. 1990). The matrix compartment receives the bulk of sensorimotor striatal afferents and appears to be strongly regulated by both DA and ACh.
Regions
In primates, the dorsal striatum is divided by the internal capsule into the medially located caudate nucleus and the laterally positioned putamen. In rodents, descending motor axon bundles perforate the striatum, yielding no clear division between dorsomedial and dorsolateral striatum. However, these striatal regions (Figure 1e) are anatomically and functionally distinct in both rodents and primates ( Joel & Weiner 1994, Parent & Hazrati 1995, Yin & Knowlton 2006); the dorsomedial striatum receives inputs primarily from association cortices (Goldman & Nauta 1977, McGeorge & Faull 1989, Ragsdale & Graybiel 1981) and the dorsolateral striatum receives inputs from sensorimotor cortex (Kunzle 1975, Liles & Updyke 1985, McGeorge & Faull 1989). The ventral striatumor nucleus accumbensrepresents a third subdivision of the striatum, with distinct properties from both the dorsomedial and the dorsolateral striata (Nicola 2007). The ventral striatum, like the patches of the dorsal
striatum, receives glutamatergic inputs from frontal cortex and limbic regions (Brog et al. 1993). However, the dopaminergic innervation of the ventral striatum derives from the ventral tegmental area, a separate midbrain nucleus adjacent to the SNc (Fields et al. 2007). The ventral striatum can be further subdivided into core and shell regions: Core regions display similarity to the dorsal striatum, and shell regions are more similar to the amygdala (Zahm 2000). In addition to their connectivity, striatal regions differ in several other important aspects, including cell-type prevalence and gene expression patterns. Parvalbumin-positive (FS) interneurons are enriched in the lateral striatum and are much less evident in the medial striatum (Kita et al. 1990). In contrast, somatostatin-positive (LTS) interneurons have a complementary distribution, with higher densities in the medial striatum and the ventral striatum (Gerfen et al. 1985). Differences in regional density and prevalence are species specic: Primates exhibit a higher density of interneurons than do rodents (Graveland et al. 1985, Wu and Parent 2000). In addition, primates have more calretinin-positive interneurons and also exhibit greater densities of parvalbumin-positive interneurons in the dorsomedial striatum, in contrast to rodents (Wu & Parent 2000). Striatal region gene expression patterns also differ. For example, cannabinoid CB1 receptors are highly expressed in ventral and dorsolateral striatum, but not dorsomedial striatum (Herkenham et al. 1991), whereas calbindin is highly expressed in dorsomedial striatum but only weakly expressed in dorsolateral striatum (Gerfen et al. 1985).
STRIATAL NEUROMODULATORS Dopamine

DA plays a fundamental role in normal basal ganglia function and movement (Heien & Wightman 2006, Nicola et al. 2000, Schultz 2007b). The striatum is densely innervated by dopaminergic bers originating in the SNc (dorsal striatum) and ventral tegmental area
(ventral striatum), and striatal MSNs, GABAergic interneurons, and cholinergic interneurons all express DA receptors. The axons of DA neurons arborize extensively in the striatal neuropil (Prensa & Parent 2001), giving rise to a dense matrix of en passant terminals capable of releasing DA over large regions of striatum. Dopaminergic boutons represent nearly 10% of all striatal synapses (Groves et al. 1994), and the nearest-neighbor distance between dopaminergic boutons is only 1.18 m (Arbuthnott & Wickens 2007). Although some of these terminals are found directly adjacent to cortical synapses at spine necks (Freund et al. 1984, Smith et al. 1994), it is clear that DA reuptake mechanisms are not robust enough to limit spillover away from release sites, suggesting that DA acts to some degree via volume transmission (Cragg & Rice 2004). Consistent with this hypothesis, most DA receptors are located extrasynaptically (Yung et al. 1995), where they have been linked to modulation of dendritic conductances and synaptic integration (Nicola et al. 2000). Midbrain DA neurons are spontaneously active at low frequencies (18 Hz) in vivo. This ring maintains a tonic DA tone that is critical for normal striatal function (Schultz 2007b), most likely by activating high-afnity Gi coupled dopamine D2-type receptors (D2D4) (Richeld et al. 1989). In response to behaviorally relevant stimuli (Schultz 2007a), dopaminergic neurons re bursts of action potentials that briey elevate striatal extracellular DA. These phasic spikes of DA are capable of activating lower-afnity Gs -coupled dopamine D1-type receptors (D1, D5) (Richeld et al. 1989). In addition, dopaminergic tone can be modulated on longer timescales in response to behavioral states including uncertainty, stress, or reward (Schultz 2007a). DA receptors are present in every cell type in the striatum, although different cell types express different DA receptor subtypes. Striatonigral and striatopallidal MSNs contain transcripts for both D1- and D2-class DA receptors, with 10%20% overlap of D1 and D2 receptor transcripts (Surmeier et al.
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1996). However, immunohistochemical studies indicate only a 1% overlap between D1 and D2 (Ince et al. 1997), implying signicant posttranscriptional control of DA receptor expression in MSNs. The extent of D3D5 receptor expression in MSNs remains unclear. Immunohistochemical and functional evidence indicates that striatal GABAergic interneurons express primarily D5 receptors (Centonze et al. 2003a. Rivera et al. 2002), whereas cholinergic interneurons express both D2 and D5 receptors (Yan et al. 1997, Yan & Surmeier 1997).
Acetylcholine
ACh represents a second major striatal neuromodulator (Calabresi et al. 2000, Zhou et al. 2002), which is released into the extracellular space by tonically active cholinergic interneurons (Bolam et al. 1984, Wilson et al. 1990). Although cholinergic interneurons constitute less than 1% of all striatal neurons (Rymar et al. 2004), their dense and extensive axonal arborization ensures widespread release of ACh, which like DA may act locally on MSN synapses (Izzo & Bolam 1988) and have a more widespread inuence via volume transmission (Contant et al. 1996). However, ACh is rapidly degraded by an efcient extracellular enzyme, acetylcholinesterase, which may serve to limit ACh diffusion. In vivo, 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. 1995, Apicella et al. 1991, Kimura 1986), suggesting that this pause in cholinergic interneuron ring may be associated with behaviorally signicant cues. The pause appears to require coordinated synaptic inputs from both the SNc and intralaminar thalamic nuclei (Aosaki et al. 1994a, Matsumoto et al. 2001), although the precise mechanisms have yet to be determined (Bennett & Wilson 1998). ACh acts at both nicotinic (nAChR) and muscarinic (mAChR) receptors in the striatum. Nicotinic receptors are pentameric ligandgated ion channels, which are expressed widely
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in the nervous system, particularly in presynaptic terminals where they can enhance neurotransmitter release (Zhou et al. 2002). In the striatum, nicotinic receptors are expressed mainly in presynaptic DA terminals and FS interneurons (Koos & Tepper 2002, Schwartz et al. 1984, Zhou et al. 2002), although there is some evidence for expression on glutamatergic terminals, as well. In contrast, mAChRs are expressed widely on MSNs, cholinergic interneurons, and GABAergic interneurons. All ve muscarinic receptor subtypes (M1M5) are expressed in the dorsal striatum. M1, M3, and M5 receptors are Gq -coupled, whereas M2 and M4 receptors are Gi -coupled. M1 receptors are expressed in all MSNs, whereas M4 receptors are restricted to direct-pathway MSNs (Ince et al. 1997, Yan et al. 2001). In contrast, M2 receptors are found exclusively in cholinergic interneurons (Bernard et al. 1992, Weiner et al. 1990), wherealong with M4 receptorsthey function as cholinergic autoreceptors regulating ACh release (Alcantara et al. 2001, Yan & Surmeier 1996).
MEDIUM SPINY NEURONS Membrane Properties

The principal neurons of the striatum are the MSNs, which represent >95% of all striatal neurons and form the sole output to downstream basal ganglia nuclei (Kemp & Powell 1971a, Rymar et al. 2004). All MSNs share a similar morphology, but they can be classied into at least two types on the basis of their axonal projection patterns (Smith et al. 1998). Striatonigral MSNs project directly to basal ganglia output nuclei: internal globus pallidus (primates)/entopeduncular nucleus (rodents) and the SNr. In contrast, striatopallidal MSNs send axons to the GP, thus only indirectly connecting to basal ganglia output nuclei through a polysynaptic pathway. Striatopallidal MSNs appear to receive a bulk of the sensorimotor corticostriatal afferents (Berretta et al. 1997, Parthasarathy & Graybiel 1997). This class of afferents project
topographically from cortex to the striatum; for example, projections from neighboring barrels in mouse somatosensory cortex are targeted to discrete neighboring regions of striatal neuropil (Wright et al. 1999). Additionally, both classes of MSNs receive synapses from interneurons as well as axon collaterals from other MSNs (Tepper et al. 2004). Although MSNs do not represent a homogenous population, they do share a number of physiological properties, and a vast majority of studies have considered them as a single cell type. MSNs are characterized by their hyperpolarized resting membrane potential and low input resistance (Kita et al. 1984), as well as by several types of potassium conductances that shape their characteristic ring patterns (Nisenbaum & Wilson 1995) (Figure 2a). At rest, inwardly rectifying potassium channels (Kirs) contribute to their negative resting potential, low input resistance, and rapid membrane time constants (Mermelstein et al. 1998, Nisenbaum et al. 1996, Uchimura et al. 1989). Membrane depolarization inactivates Kirs and activates both fast- (Kv4.2) and slowinactivating (Kv1.2) A-type potassium currents, as well as a persistent potassium conductance (Kv7), which together yield a slow depolarization and delay to the initial spike (Nisenbaum et al. 1996; Shen et al. 2004, 2005; Surmeier et al. 1989, 1991; Tkatch et al. 2000). Depolarization and spiking also yield calcium inux, which can activate both small- and large-conductance calcium-activated potassium channels (Bargas et al. 1999) and limit MSN ring rates. 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. 1998). By using post hoc reverse-transcriptase polymerase chain reaction (RT-PCR) analysis to identify MSN subtypes, striatopallidal MSNs were found to exhibit Kir currents that inactivated more readily at hyperpolarized potentials. Given the hyperpolarized resting potential of typical MSNs, a reduction in available Kirs in
a
20 mV 100 ms
MSN
FS
LTS
d
TAN
Figure 2 Firing properties of striatal neurons. Whole-cell current-clamp recordings were performed from different striatal cell types. MSNs (a) exhibit low input resistance, inward rectication, and a long delay to initial spiking. FS interneurons (b) have low input resistance and a characteristic rapid ring pattern. LTS interneurons (c) have high input resistance and a sustained plateau potential that persists after the end of current injections. LTS interneurons also display rebound spiking following hyperpolarizations (not shown here). Tonically active cholinergic interneurons (TANs) (d ) exhibit a prominent hyperpolarization-activated current and broad spikes with long spike afterhyperpolarizations.
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Inwardly rectifying potassium channels: a voltage-sensitive potassium channel that is permeable to potassium at hyperpolarized potentials, but blocked by intracellular polyamines at depolarized potentials
Calcium-permeable AMPA receptors: GluR2-lacking receptors that exhibit calcium permeability and strong inward rectication that arises from block by intracellular polyamines at depolarized potentials
striatopallidal MSNs could signicantly increase their excitability. Consistent with this nding, a more recent study using BAC transgenic mice found that striatopallidal MSNs red at higher rates in response to current injections (Kreitzer & Malenka 2007). In addition to differences in Kir inactivation properties, striatopallidal Kirs also display relatively greater inhibition by muscarinic M1 receptors than do striatonigral neurons (see below for further discussion) (Shen et al. 2007). Thus, Kir properties in striatopallidal MSNs contribute to their increased excitability, although excitability differences persist even during large current injections that signicantly depolarize MSNs and should block Kirs (Kreitzer & Malenka 2007), suggesting that other factors may be important.
Up and Down States

Early in vivo studies of striatal MSNs noted irregular rhythmic ring 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), which were subsequently termed Down and Up states. Spiking was observed only during Up states, although not every Up state yielded a spike, and even quiescent MSNs exhibited subthreshold membrane potential uctuations. Recent work indicates that Up and Down states are most prominent under anesthesia and during slow-wave sleep. In contrast, the waking state is characterized by noisy MSN membrane uctuations. State transitions, although still present, are less obvious under these conditions (Mahon et al. 2006). 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). 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. However, if sufcient numbers of glutamatergic inputs become active, MSNs can be depolarized
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enough to block Kirs, shifting MSNs into the Up state (Blackwell et al. 2003). The Up state persists as long as sufcient excitatory drive is present to maintain depolarization. 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). Up states correlated among striatal MSNs, although individual spikes did not (Stern et al. 1998), consistent with the hypothesis that MSNs receive converging inputs from cortical neurons that re in a correlatedbut not totally synchronousmanner. Up state transitions also change the properties of synaptic conductances. In the Down state, excitatory postsynaptic potentials are mediated almost entirely by AMPA receptors. At depolarized Up state potentials, NMDA receptors are also activated, yielding slower excitatory potentials that summate more readily. Up state transitions also shift the dominant source of synaptic calcium inux from calcium-permeable AMPA receptors to NMDA receptors (Carter & Sabatini 2004). Additionally, MSNs express low-voltageactivated l-type calcium channels (Cav1.3), which are activated in the Up state (Carter & Sabatini 2004) and are required for the induction of striatal long-term depression (Choi & Lovinger 1997, Kreitzer & Malenka 2005).
Neuromodulation
Striatal MSNs exhibit numerous ionic conductances that shape their ring properties, and many of these conductances are sensitive to neuromodulators such as DA and ACh. Striatonigral MSNs express D1 receptors, which regulate sodium, potassium, and calcium channels. Activation of D1 receptors reduces sodium currents (Schiffmann et al. 1995, Surmeier et al. 1992) and enhances Kirs (Pacheco-Cano et al. 1996), both of which are predicted to reduce MSN excitability. However, D1 receptors also enhance l-type currents that are activated in the Up state (Carter & Sabatini 2004,
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Surmeier et al. 1995), giving rise to an enhancement of ring when neurons are depolarized (Hernandez-Lopez et al. 1997). Moreover, D1 receptors block a slowly inactivating potassium conductance, which should also enhance ring in the Up state (Nisenbaum et al. 1998). Together, these ndings suggest that D1 receptor activation acts as a lter to limit Up state transitions to periods of signicant excitatory drive; however, once in the Up state, D1 receptors facilitate the ring of striatonigral MSNs. In contrast, D2 receptors, which are expressed at high levels in striatopallidal MSNs, mainly inhibit MSN ring. Although they reduce Kir currents (Uchimura & North 1990), which should facilitate Up state transitions, they also inhibit l-type currents and reduce spiking in the Up state (Hernandez-Lopez et al. 2000). It is intriguing to note that D2 receptors, like D1 receptors, exhibit opposite effects in the Down and Up states. Thus, D2 receptors may reduce the excitatory drive necessary for Up state transitions on a timescale of seconds, while increasing the requirement for synchrony on the milliseconds timescale to drive spiking. Striatal D2 receptors have also been linked to mobilization of endocannabinoids (Giuffrida et al. 1999, Yin & Lovinger 2006), 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). 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). Cholinergic modulation of MSNs is mediated by muscarinic ACh receptors (Yan et al. 2001). Activation of M1 receptors, which are expressed by striatopallidal and striatonigral MSNs, shifts the activation and inactivation of transient A-type potassium currents to more hyperpolarized potentials (Akins et al. 1990). Thus, when MSNs are in the Down state, A-type potassium currents are partially activated, which will tend to keep MSNs hyperpolarized. However, if excitatory synaptic drive
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. However, M1 receptor activation inhibits Kirs via phospholipase C activation and depletion of phosphatidylinositol biphosphate (PIP2 ) (Shen et al. 2007). This modulation is selective for striatopallidal MSNs because of their high level of Kir2.3 expression, which is particularly sensitive to PIP2 depletion (Du et al. 2004). M1 activation also blocks a persistent potassium current mediated by Kv7 channels (Shen et al. 2005). Furthermore, M1 activation inhibits N- and P/Qtype calcium channels that couple to calciumactivated potassium channels in MSNs, leading to enhanced spiking. Together, these ndings indicate that M1 activation increases MSN excitability and also enhances the likelihood of state transitions in striatopallidal MSNs. M1 receptors have also been linked to endocannabinoid production in MSNs, although their particular role has been disputed. In the hippocampus and cerebellum, activation of Gq coupled receptors such as M1/3 or mGluR1/5 stimulates endocannabinoid production via phospholipase C. M1 activation in striatal MSNs also facilitated depolarization-evoked endocannabinoid release (Narushima et al. 2007). However, 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. 2006). Further studies will be required to clarify this issue.
INTERNEURONS Fast Spiking Interneurons

FS interneurons represent only a few percent of all striatal neurons (Kita et al. 1990, Rymar et al. 2004), yet they are critical for regulating striatal output. Mice with decreased numbers of striatal FS neurons exhibit procedural learning decits (Marrone et al. 2006), and injections of GABAA antagonists into the putamen increase MSN ring (Mallet et al. 2005), inhibit
spiking in the SNr (Yamada et al. 1995), and induce dystonia (Yamada et al. 1995, Yoshida et al. 1991). Striatal FS interneurons share properties similar to FS interneurons in the hippocampus and cortex, such as short-duration spikes, high-frequency ring, and gap junctions with other FS interneurons (Kawaguchi 1993, Kita et al. 1990) (Figure 2b). They are relatively enriched in dorsolateral striatum (Bennett & Bolam 1994, Kita et al. 1990), suggesting that they play a key role in sensorimotor integration. FS interneurons receive excitatory synapses from both cortex (Kita 1993, Lapper et al. 1992, Ramanathan 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 al. 1998). Unlike MSNs, which receive small numbers of inputs from large numbers of afferents, FS interneurons often receive multiple synaptic contacts from individual afferent bers (Ramanathan et al. 2002). Thus, they do not require the same degree of input synchrony that MSNs need to trigger a spike. FS interneurons mainly target MSNs, where they form numerous proximal synapses capable of inhibiting the generation of action potentials in MSNs (Bennett & Bolam 1994, Kita 1993, Koos & Tepper 1999, Mallet et al. 2005). This inuence arises from the presence of multiple synaptic contacts on MSNs, as well as from their proximal location on MSN somata and dendrites (Kubota & Kawaguchi 2000). Researchers estimate that a single MSN receives inhibitory synapses from 427 FS interneurons, whereas a single interneuron connects to 135541 MSNs (Koos & Tepper 1999). MSN synapses onto interneurons were not observed. In addition, FS interneurons display dendritic gap junctions and exhibit electrotonic coupling (Kita et al. 1990, Koos & Tepper 1999), which can lead to ring synchrony among local interneuron populations. However, even bursts in single interneurons can signicantly delay spiking in MSNs (Koos & Tepper 1999). In vivo, FS interneurons exhibit higher ring frequencies than do MSNs and may entrain oscillations between cortex and striatum (Berke et al. 2004).
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Desynchronized cortical activity enhances interneuron spiking and leads to a dramatic reduction in MSN spiking activity (Mallet et al. 2005) owing to both a reduced excitatory drive on MSNs and an increased inhibitory tone. FS interneurons have faster response latencies than do MSNs in vivo and may limit the duration of MSN spiking. Given the prominent role of FS interneurons in regulating MSN spiking, modulation of their ring properties by neuromodulators should be important for striatal function. DA excites FS interneurons via D5 receptor activation (Bracci et al. 2002, Centonze et al. 2003b) and also via D2-mediated inhibition of GABAergic afferents onto FS interneurons (Bracci et al. 2002). ACh also excites FS interneurons through a direct depolarization mediated by nondesensitizing nicotinic receptors. Thus, elevations in ACh are predicted to excite FS interneurons directly. ACh may also indirectly facilitate FS ring by enhancing DA release via presynaptic nicotinic receptors (Zhou et al. 2002). In contrast, elevated DA would directly excite FS interneurons but simultaneously inhibit cholinergic interneurons (see below), which could mitigate DA-mediated FS excitation to some degree.
Low-Threshold Spiking Interneurons

A second type of GABAergic striatal interneuron is the LTS cell. LTS interneurons represent a few percent of striatal neurons (Rymar et al. 2004) and exhibit fewer dendritic branches, as well as less dense and more extensive axonal arborizations relative to FS interneurons (Kawaguchi 1993, Vuillet et al. 1989). LTS interneurons express somatostatin, neuropeptide Y, and nitric oxide synthase (Chesselet & Graybiel 1986, Kubota et al. 1993, Smith & Parent 1986, Vincent et al. 1983), which likely plays a role in the induction of striatal long-term plasticity (Calabresi et al. 1999). Like FS interneurons, LTS interneurons are innervated by glutamatergic afferents from both cortex and thalamus, and in turn form synapses onto MSNs (Sidibe & Smith 1999, Vuillet et al.
1989). However, some LTS interneurons also appear to receive signicant dopaminergic innervation (Hidaka & Totterdell 2001, Kubota et al. 1988). A second population of LTS interneurons may correspond to calretininpositive interneurons, which have not been well characterized (Bennett & Bolam 1993, Tepper & Bolam 2004) but appear to lack significant thalamic innervation (Sidibe & Smith 1999). Electrophysiologically, LTS interneurons are characterized by their plateau potentials and low-threshold spikes; in addition, these interneurons display higher input resistances and relatively depolarized resting potentials (Kawaguchi 1993) (Figure 2c). Modulation of striatal interneurons has not been well characterized, although their innervation by dopaminergic axons is prominent in both dorsal and ventral striata. LTS interneurons, like other striatal interneurons, express D5 receptors (Rivera et al. 2002). Activation of these receptors depolarizes LTS interneurons, leading to signicant increases in spiking (Centonze et al. 2002), although the precise signaling mechanisms are not clear. Muscarinic M1 and M2 receptors are also expressed in LTS interneurons (Ariano & Kenny 1989; Bernard et al. 1992, 1998), but their physiological roles remain unknown.
Cholinergic Interneurons
Cholinergic interneurons, also known as large aspiny neurons or tonically active neurons, constitute only 1%2% of striatal cells (Kemp & Powell 1971a), but their inuence is signicant. They have large (2050 m diameter) cell bodies and widespread axonal elds, which form synapses primarily on MSNs (Bolam et al. 1984, Izzo & Bolam 1988, Phelps et al. 1985), but also on FS interneurons (Chang & Kita 1992, Koos & Tepper 2002). Cholinergic interneurons receive only sparse excitatory innervation, which derives primarily from the thalamus (Lapper & Bolam 1992) and, to a lesser extent, the cortex (Thomas et al. 2000). They also receive inhibitory synapses from MSNs (Bolam et al. 1986). Cholinergic interneurons
can be electrophysiologically distinguished by their depolarized resting potential and highinput resistance (Kawaguchi 1993) (Figure 2d ). Cholinergic interneurons re spontaneously in vivo owing to their expression of sodium currents and hyperpolarization-activated cation currents (Bennett et al. 2000). Their ring rates are limited to 210 Hz by a prominent afterhyperpolarization following each spike, owing primarily to calcium-activated potassium channels (Kawaguchi 1992, 1993; Wilson et al. 1990; Wilson & Goldberg 2006). A characteristic feature of cholinergic interneurons in vivo is their pause in tonic ring in response to salient cues, including reward and reward prediction (Aosaki et al. 1994b, Graybiel et al. 1994, Morris et al. 2004). Although the precise origins of this pause are still unclear, it requires both intact thalamic and dopaminergic innervation to occur (Aosaki et al. 1994a, Matsumoto et al. 2001). The instrinsic properties of cholinergic interneurons are also critical. Cholinergic interneurons, like MSNs, express Kirs that become unblocked at hyperpolarized potentials, and these serve to amplify and prolong the effects of hyperpolarizing inputs (Wilson 2005). Cholinergic interneurons express both D2 and D5 receptors, as well as M2 and M4 mAChRs (Bergson et al. 1995, Hersch et al. 1994, Levey et al. 1993). D5 receptor activation depolarizes cholinergic interneurons through a cAMP-dependent mechanism (Aosaki et al. 1998), whereas D2 signaling mediates an inhibition of voltage-sensitive sodium channels that reduces excitability (Maurice et al. 2004). Thus, D1-type and D2-type dopamine receptors exert opposite effects on excitability within individual cholinergic interneurons. Muscarinic M2 and M4 receptors, like D2 receptors, reduce excitability albeit through a different mechanism involving activation of a potassium conductance (Calabresi et al. 1998). M2 receptors may also function as presynaptic autoreceptors (Hersch et al. 1994) regulating ACh release via direct G/-mediated inhibition of presynaptic calcium channels (Yan & Surmeier 1996).
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
M1
q
M2
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TAN
Figure 3 Dopaminergic and cholinergic modulation of striatal neurons. Schematic depicting different types of striatal neurons and their complement of dopamine and acetylcholine receptors. Striatopallidal (indirect-pathway) and striatonigral (direct-pathway) MSNs are shown in gray. FS and LTS interneurons are depicted in blue and red, respectively, and the cholinergic neuron is shown in green. G proteincoupled receptors are displayed with their associated G-protein: Gs (magenta), Gi ( purple), or Gq (blue). FS interneurons also express the ionotropic nicotinic ACh receptor.
CONCLUSIONS
Signicant heterogeneity exists within both interneuron and projection neuron populations in the striatum. In addition to differences in synaptic convergence, intrinsic membrane properties, and in vivo ring patterns, each type of striatal neuron expresses a distinct complement of DA and ACh receptors (Figure 3). Thus, changes in ACh or DA levels will exert complex effects on striatal neuron activity, as well as on DA and ACh release itself. For example, increased dopaminergic tone is predicted to increase D2 receptor activation selectively, given its relatively higher afnity for DA (Richeld et al. 1989). This would lead to decreased striatopallidal MSN output, decreased cholinergic interneuron activity, and subsequent reductions in cholinergic tone. However,
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reduced autoinhibition of ACh release might compensate to some extent for this reduction in cholinergic tone. Reduced depolarization of FS interneurons via nicotinic receptors would also occur, rendering them less excitable. Similarly, reduced activation of presynaptic nicotinic receptors on dopamine terminals would reduce DA release itself, and the system would reestablish an equilibrium level of DA and ACh. In contrast, brief spikes in DA concentrations could exert signicantly different effects. Large increases in DA yield both D1 and D2 receptor activation. Thus, striatonigral MSN output would be enhanced, whereas striatopallidal MSNs would be inhibited. Excitability of both FS and LTS interneurons would be increased, yielding more powerful feedforward inhibition and increased temporal precision of MSN
spiking output. Cholinergic interneurons would exhibit more complex changes owing to the opposing actions of simultaneous D2 and D5 receptor activation. Given the diversity of striatal neurons and their responses to various neuromodulators, it is also apparent that signicant caution is required in experimental design and data interpretation when performing pharmacological manipulations in the intact striatum. Interestingly, diseases of the striatum such as Parkinson disease and Huntington disease selectively affect particular neuronal subtypes. Recent evidence indicates that striatopallidal MSNs undergo spine loss following dopamine depletion, whereas neighboring striatonigral MSNs retain normal morphology (Day et al. 2006). At the same time, striatopallidal MSNs exhibit increased ring rates (Mallet et al. 2006), which suggests that this decrease in spine density may reect a compensatory mechanism aimed at reducing overexcitation. In
Huntington disease, striatopallidal MSNs are selectively vulnerable to cell death (Mitchell et al. 1999, Reiner et al. 1988), although both types of MSNs eventually degenerate. In contrast, striatal interneurons are selectively spared (Cicchetti et al. 1996, Ferrante et al. 1985). The increased prevalence of interneurons in Huntington disease could exacerbate striatal decits arising from loss of MSNs (Cepeda et al. 2004). Heterogeneity among neuronal populations is therefore a critical factor to consider when studying striatal function. However, the physiological properties of striatal neurons also depend on the properties of their synaptic inputs. In addition, a host of other neuromodulators including adenosine, endocannabinoids, nitric oxide, and various neuropeptides play important roles in shaping the physiology of striatal neurons. Future studies will be required to understand how these various factors interact to regulate basal ganglia circuit function.
DISCLOSURE STATEMENT
The author is not aware of any afliations, memberships, funding, or nancial holdings that might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
I thank members of my laboratory for their critical reading of the manuscript and Carlo Tringale for administrative assistance. Our research on this subject is supported by the Pew Charitable Trusts, the CHDI Foundation, and The J. David Gladstone Institutes. LITERATURE CITED
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Annual Review of Neuroscience
Contents
Volume 32, 2009
Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage Michael Costigan, Joachim Scholz, and Clifford J. Woolf p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1 Synaptic Mechanisms for Plasticity in Neocortex Daniel E. Feldman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p33 Neurocognitive Mechanisms in Depression: Implications for Treatment Luke Clark, Samuel R. Chamberlain, and Barbara J. Sahakian p p p p p p p p p p p p p p p p p p p p p p p p p p57 Using Diffusion Imaging to Study Human Connectional Anatomy Heidi Johansen-Berg and Matthew F.S. Rushworth p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p75 Serotonin in Affective Control Peter Dayan and Quentin J.M. Huys p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p95 Physiology and Pharmacology of Striatal Neurons Anatol C. Kreitzer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 127 The Glial Nature of Embryonic and Adult Neural Stem Cells Arnold Kriegstein and Arturo Alvarez-Buylla p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 149 Representation of Number in the Brain Andreas Nieder and Stanislas Dehaene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 185 Neuronal Gamma-Band Synchronization as a Fundamental Process in Cortical Computation Pascal Fries p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 209 The Neurobiology of Individual Differences in Complex Behavioral Traits Ahmad R. Hariri p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 225 The Science of Neural Interface Systems Nicholas G. Hatsopoulos and John P. Donoghue p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 249 The Neuropsychopharmacology of Fronto-Executive Function: Monoaminergic Modulation T.W. Robbins and A.F.T. Arnsten p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 267
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The Inuence of Stress Hormones on Fear Circuitry Sarina M. Rodrigues, Joseph E. LeDoux, and Robert M. Sapolsky p p p p p p p p p p p p p p p p p p p p p p p 289 The Primate Cortical Auditory System and Neural Representation of Conspecic Vocalizations Lizabeth M. Romanski and Bruno B. Averbeck p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 315 Establishment of Axon-Dendrite Polarity in Developing Neurons Anthony P. Barnes and Franck Polleux p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 347 Axon Growth and Guidance: Receptor Regulation and Signal Transduction Michael ODonnell, Rebecca K. Chance, and Greg J. Bashaw p p p p p p p p p p p p p p p p p p p p p p p p p p p p 383 Cerebellum and Nonmotor Function Peter L. Strick, Richard P. Dum, and Julie A. Fiez p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 413 Advances in Light Microscopy for Neuroscience Brian A. Wilt, Laurie D. Burns, Eric Tatt Wei Ho, Kunal K. Ghosh, Eran A. Mukamel, and Mark J. Schnitzer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 435 Indexes Cumulative Index of Contributing Authors, Volumes 2332 p p p p p p p p p p p p p p p p p p p p p p p p p p p 507 Cumulative Index of Chapter Titles, Volumes 2332 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 511 Errata An online log of corrections to Annual Review of Neuroscience articles may be found at http://neuro.annualreviews.org/
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Kreitzer Physiology and Pharmacology of Striatal Neurons

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Kreitzer Physiology and Pharmacology of Striatal Neurons

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ANNUAL REVIEWS

Physiology and Pharmacology of Striatal Neurons

SNc: Substantia Nigra pars compacta ChAT: choline acetyltransferase

STRIATAL NEUROMODULATORS Dopamine

MEDIUM SPINY NEURONS Membrane Properties

www.annualreviews.org Striatal Physiology and Pharmacology

Up and Down States

INTERNEURONS Fast Spiking Interneurons

Low-Threshold Spiking Interneurons

www.annualreviews.org Striatal Physiology and Pharmacology

Annual Review of Neuroscience

Volume 32, 2009

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