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Local and afferent synaptic pathways in the striatal microcircuitry
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ScienceDirect Local and afferent synaptic pathways in the striatal microcircuitry Gilad Silberberg1 and J Paul Bolam2 The striatum is the largest structure of the basal ganglia, receiving synaptic input from multiple regions including the neocortex, thalamus, external globus pallidus, and midbrain. Earlier schemes of striatal connectivity presented a relatively simple architecture which included primarily excitatory input from the neocortex, dopaminergic input from the midbrain, and intrastriatal connectivity between projection neurons and a small number of interneuron types. In recent years this picture has changed, largely due to the introduction of new experimental methods to reveal cell types and their connectivity. The striatal microcircuit is now considered to consist of several newly defined neuron types which are intricately and selectively interconnected. New afferent pathways have been discovered, as well as novel properties of previously known afferents such as the midbrain dopaminergic inputs. In this review we aim to provide a summary of these recent discoveries. Addresses 1 Department of Neuroscience, Karolinska Institutet, Retzius va¨g 8, Stockholm 17177, Sweden 2 Medical Research Council Brain Network Dynamics Unit, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK Corresponding author: Silberberg, Gilad ([email protected])
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nitric oxide synthase (NOS), neuropeptide-Y (NPY) and SOM, whereas others appeared to be mutually exclusive, as in the case of SOM and PV. The use of transgenic mice selectively expressing fluorescent markers under the control of promoters of specific markers has led to the identification of several classes of interneuron and enabled a systematic characterization of the various types, resulting in more refined classification schemes. Tyrosine hydroxylase-expressing interneurons
Using a BAC transgenic mouse expressing EGFP in tyrosine-hydroxylase (TH) expressing neurons (EGFPTH+), Ibanez-Sandoval and colleagues [3] defined four interneuron subtypes based on their electrophysiological properties. The interneurons are all GABAergic, most of which have novel intrinsic electrophysiological properties. TH was not co-expressed with NOS, PV, or calretinin, suggesting that this population of interneurons is indeed novel and not part of previously characterized groups. Interestingly, TH expression increased following midbrain 6-hydroxydopamine (6-OHDA) lesions, which could suggest a compensatory mechanism following dopamine depletion [4], however, the TH-expressing interneurons have been shown to release GABA but not dopamine [5] and thus represent populations of GABAergic neurons.
This review comes from a themed issue on Motor circuits and action Edited by Ole Kiehn and Mark Churchland
http://dx.doi.org/10.1016/j.conb.2015.05.002 0959-4388/# 2015 Elsevier Ltd. All rights reserved.
Striatal neuron types The striatum consists of a majority of projection neurons, the medium spiny neurons (MSNs) and a small, yet diverse population of interneurons. Interneurons were initially divided into four subtypes, including three types of GABAergic interneurons, and the tonically active cholinergic interneurons [1,2]. These electrophysiologically defined subtypes also fitted a molecular profile based on immunostaining for markers such as parvalbumin (PV), calretinin (CR), somatostatin (SOM), and choline-acetyltransferase (ChAT). Some of the markers used in the characterization of the neurons were co-localised such as Current Opinion in Neurobiology 2015, 33:182–187
NPY-expressing interneurons
Using a similar approach to that used in the discovery of TH-positive interneurons, the use of a transgenic GFPNPY reporter mouse line has revealed the existence of at least two distinct types of interneurons that express NPY [6]. One type was the previously described ‘low-threshold spiking’ (LTS) interneuron and the other was defined as ‘NPY-neurogliaform’ (NPY-NGF), based on its similarity to the cortical neurogliaform interneurons. The two NPYGFP interneurons exhibit different electrophysiological, morphological, molecular, and synaptic profiles, thus justifying the division into two distinct subtypes. One important feature of the NPY-LTS interneurons recorded in mouse striatum is their tonic activity [7], making them the second tonically active interneuron type in the striatal microcircuit in addition to cholinergic interneurons [8]. Interestingly, in rats, no NPY-NGF have been reported, and NPY interneurons expressing NOS do not display tonic discharge in vivo [9]. 5HT3a-expressing interneurons
Using BAC transgenic eGFP mouse lines, Fishell, Rudy, and colleagues have identified a population of neocortical www.sciencedirect.com
Synaptic pathways in the striatal microcircuitry Silberberg and Bolam 183
GABAergic interneurons that express the 5HT3a serotonin receptor [10,11]. In the neocortex, the 5HT3a-expressing neurons are prevalent in superficial cortical layers and together with the PV- and SOM-expressing interneurons, could account for almost all GABAergic interneurons. In the same mouse line 5HT3a-expressing interneurons were also characterized in the striatum, revealing a large and diverse population [12]. Similar to TH-expressing interneurons, striatal 5HT3a-EGFP interneurons exhibit distinct electrophysiological subtypes, as well as different co-expression patterns with PV, NOS, TH, and calretinin. The greatest degree of overlap was between 5HT3a and PV, which was also reflected in the fast-spiking electrophysiological phenotype of more than 30% of recorded 5HT3a-GFP interneurons. One subtype of 5HT3a interneuron was shown to be activated by nicotinic input from cholinergic interneurons and provides GABAergic input to MSNs [13]. Summary
The number of striatal neuron subtypes is larger than previously assumed and is likely to change in the coming years and vary according to different classification schemes used in the field. The classification is not always straightforward due to the overlap of the different molecular, electrophysiological, and morphological properties, as well as differences between species. New directions towards the resolution of cell type classification may now
be provided by single cell RNA sequencing [14] and fate mapping [15] studies, where the electrophysiological, morphological, and network properties of neurons are correlated to their developmental origin and molecular fingerprint.
Striatal interneuron connectivity Striatal interneurons of the different types are instrumental in sculpting striatal output via intrastriatal synaptic connections. Perhaps the most prominent of the intrastriatal synapses are the GABAergic synapses formed between FS interneurons and MSNs [16] (Figure 1). These synapses are characterized by a very high connection probability, with each FS interneuron contacting a majority of its neighboring (within 100 mm radius) MSNs [17]. A single FS-MSN IPSP is sufficient to alter the discharge pattern of the postsynaptic MSN [16,18]. The same presynaptic FS interneurons contact both direct and indirect pathway MSNs, with preference towards direct pathway (D1 expressing MSNs) [17,19], which is reversed following 6-OHDA induced dopamine depletion by selective increase in the connections onto D2 MSNs [20]. Striatal FS interneurons share many of the morphological, electrophysiological, and synaptic properties with cortical FS interneurons, however, one striking difference is the lack of reciprocity between them and their targeted projection neurons. In the neocortex there is a high degree of reciprocity between FS
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A selective ‘blanket’ of inhibition by striatal PV interneurons. (a) Schematic representation of an experiment showing robust inhibition of MSNs by optogenetic activation of fast-spiking PV-expressing interneurons and avoidance of a simultaneously recorded neighboring cholinergic interneuron (CHIN). (b) Blanket of feed-forward inhibition by PV interneurons onto MSNs, with ‘holes’ representing the avoided cholinergic interneurons.Adapted from [27,28]. www.sciencedirect.com
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interneurons and pyramidal cells [21–25], whereas striatal FS interneurons strictly provide unidirectional ‘feed-forward’ inhibition of MSNs, with no report so far, of MSN to FS synaptic interactions [16,17,19,26]. In neocortex as well as striatum, FS interneurons appear to provide a so called ‘blanket’ of inhibition covering neighboring projection neurons [23,27]. However, this inhibitory blanket does not equally influence all types of neighboring neurons but rather displays selectivity in its targeting. In the striatum, PV interneurons selectively avoid cholinergic interneurons, while robustly inhibiting neighboring MSNs [28], thus exhibiting a high degree of selectivity in the local circuitry, similar to the local target preference found in neocortical interneurons [29] (Figure 1). Another source of inhibitory input to MSNs is indirectly evoked by striatal cholinergic interneurons. This class of neuron provides nicotine-receptor dependent disynaptic inhibition of both types of MSN upon synchronized activation [30] (Figure 2). The GABAergic response
of MSNs can be divided into two components based on the synaptic kinetics, in which the slow component (decay time constant of 80 ms) is mediated by NPYNGF interneurons (Figure 2). NPY-NGF interneurons receive direct nicotinic excitation from cholinergic interneurons and synchronous optogenetic activation of several cholinergic interneurons can evoke discharge that delivers the slow GABAA inhibition. Activation of cholinergic interneurons also results in a fast GABAA component which is likely to be mediated by axo-axonic activation of afferent midbrain axons [31] (see ‘Striatal afferents’ section).
Striatal afferents The striatum acts as a hub upon which numerous streams of information converge from different brain regions, mediated by different types of neurotransmitter. In recent years several new pathways have been discovered and characterized that are likely to have profound effects on the flow of information through the striatum (Figure 2). Glutamatergic afferents
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Afferent striatal pathways. Schematic of striatal afferents from GPe [52], PPN [54], and SNc [43,46]. Intrastriatal connections between NPY-NGF and 5HT3a interneurons, and cholinergic interneurons [30,42] underlying disynaptic pathways between cholinergic interneurons and MSNs [31,60]. The partial innervation of MSNs by afferent projections from GPe and SNc is made only for illustration purposes. Abbreviations: GPe, globus pallidus external segment; PPN, pedunculopontine nucleus; SNc, substantia nigra pars compacta; CHIN, cholinergic interneurons; MSN, medium spiny neurons; NPYNGF, neuropeptide-Y expressing neurogliaform interneurons; 5HT3a, 5-hydroxytryptamine 3a receptor expressing interneurons; PV, parvalbumin expressing interneurons; GP-TI, prototypic GPe neurons; GP-TA, atypical; arkypallidal GP neurons; Glu, glutamate; ACh, acetylcholine. Current Opinion in Neurobiology 2015, 33:182–187
Cortical input to striatum is widely considered to be the dominant driver of striatal activity, and an important aspect regarding this pathway is the target preference of cortical inputs onto different types of striatal neuron. Both direct and indirect pathway MSNs have been shown to receive cortical input, however it has been suggested that these inputs originate from different populations of cortical pyramidal neurons [32]. According to this view, direct pathway MSNs are preferentially targeted by ipsiand contralateral intra-telencephalic (IT) pyramidal neurons, whereas indirect pathway neurons are targeted by ipsilateral pyramidal tract (PT) neurons. This idea has been challenged in recent anatomical studies, where no significant difference was found in the cortical targeting of D1 and D2 MSNs [33,34]. Selective optogenetic activation of cortical afferents of IT and PT types showed that both direct and indirect pathway MSNs receive excitatory synaptic input from both corticostriatal pathways [35]. In vivo recordings of synaptic responses to sensory stimuli also do not support such an ipsilateral bias in cortical input to indirect pathway MSNs [36]. Striatal interneurons receive cortical input and display type-dependent response profiles to cortical as well as thalamic activity [9,37,38]. These differences in response profile may reflect the distinct membrane properties of the target interneurons [39] as well as differences in corticostriatal synaptic properties [40]. Glutamatergic input from thalamus also targets both direct and indirect pathway MSNs [33,41], converging with cortical input even at the single cell level [42]. In addition to the glutamatergic input from cortex and thalamus there is recent evidence in transgenic mouse lines for glutamate co-release from midbrain dopaminergic axons [43–45,46]. Such glutamate responses were www.sciencedirect.com
Synaptic pathways in the striatal microcircuitry Silberberg and Bolam 185
evoked in mouse striatum following optogenetic stimulation of dopamine axon terminals in both types of MSNs [46] as well as FS and cholinergic interneurons [43]. In adult rats, however, there is no expression of vesicular glutamate transporters in dopamine axon terminals in the dorsal or ventral striatum [47]. GABAergic afferents
The striatum consists of almost entirely GABAergic neurons, however, it also receives GABAergic afferent inputs. One source of striatal GABA is the midbrain (VTA and SNc), containing dopaminergic and GABAergic afferents. GABA has been shown to be co-released with dopamine onto both types of MSN [46] as well as cholinergic interneurons [43,48]. The striatum also receives GABAergic afferents from the midbrain that appear to target primarily cholinergic interneurons [49]. An additional source of afferent GABAergic input to the striatum originates in the external segment of the globus pallidus (GPe). Two subclasses of GABAergic neurons provide the innervation [50,51,52,53]. One type provides a fairly restricted innervation of the striatum and also innervates all caudal targets of the GPe in the basal ganglia; this type selectively targets striatal interneurons (Bevan et al., 1998). The second type, referred to as arkypallidal neurons, exclusively innervates the striatum and targets both types of MSN and interneurons [52]. Individual arkypallidal neurons give rise to as many as 13,000 synapses in the striatum and they have different electrophysiological and molecular profiles from other GPe neurons [15,52]. Cholinergic innervation of the striatum
The striatum contains some of the highest density of cholinergic markers in the brain and the only source of acetylcholine (ACh) was considered, for a long period, to be the cholinergic interneurons. However, a recent study in ChAT-cre rats, described a prominent afferent cholinergic pathway from the pedunculopontine nucleus (PPN) and the laterodorsal tegmentum (LDT) [54]. All striatal regions receive input from the PPN/LDT following a topographic organization in which dorsolateral striatum is targeted by rostral PPN and the medial and ventral striatum by LDT. The cholinergic terminals target both MSNs and interneurons, however the subtype of postsynaptic neurons is still unclear. Interestingly, cholinergic afferents from PPN appear to avoid striosomes, as revealed by mu-opioid receptor staining. Further research is required in order to determine the functional properties of the PPN cholinergic input and its interplay with striatal cholinergic interneurons. Dopamine
The striatum receives massive dopamine (DA) input from the midbrain, with individual midbrain neurons innervating large fractions of the striatum and giving rise to www.sciencedirect.com
hundreds of thousands of boutons [55–58]. DA release shapes the functional properties of striatal afferents, in particular the corticostriatal pathway [59]. Local THexpressing interneurons [45] have been shown not to release DA thus the only source of striatal DA is the axons of midbrain dopaminergic neurons. Optogenetic activation of cholinergic axons in the striatum induces release of DA in the striatum via axo-axonal interactions [60] (Figure 2). The ACh-dependent release of DA could be evoked independently of somatic discharge of the presynaptic midbrain neurons and was also triggered by activation of thalamic inputs to cholinergic interneurons. The interplay between afferent or locally induced DA release is still unclear. Local DA release largely depends on synchronous activation of cholinergic neurons and is not detected by activation of single interneurons [60]. It remains to be seen whether such a degree of synchrony emerges between cholinergic interneurons under physiological conditions. Combining the discovery of local DA release by optogenetic activation of cholinergic interneurons and the corelease of GABA by DA axons, it was then suggested that disynaptic inhibition observed between cholinergic interneurons and MSNs [30] is mediated by axo-axonic activation of DA terminals [31]. As shown earlier [30], optogenetic stimulation of cholinergic interneurons induced GABAergic responses in MSNs, that persists even in the presence of tetrodotoxin (TTX) and 4 aminopyridine (4AP), indicating an axo-axonic mechanism that is independent of action potential discharge in an intermediate GABAergic interneuron. The disynaptic inhibition was reduced following 6-OHDA lesions of the medial forebrain bundle further suggesting that it was mediated by midbrain DA axons. Interestingly, despite the observed disynaptic interactions between cholinergic interneurons and MSNs, no cross correlations in their spiking activity have been detected in awake behaving monkeys [61]. This apparent discrepancy raises the possibility that these disynaptic interactions are less common in vivo and may be activated only in particular epochs in which the synchrony of cholinergic interneurons is higher than normal [62]. Summary
The striatum is the largest nucleus of the basal ganglia, acting as a ‘hub’ onto which multiple input streams converge to interact with the intrastriatal network. The intricate connectivity patterns of the intrastriatal and afferent synapses are essential for proper function of the basal ganglia, and deviations from these patterns might lead to devastating motor and cognitive dysfunctions. The striatal microcircuitry, although comprised almost entirely by GABAergic neurons, also receives GABAergic input from several afferent pathways. In this review we aimed to highlight recent discoveries pertaining to intrastriatal and afferent synaptic Current Opinion in Neurobiology 2015, 33:182–187
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pathways, including GABAergic input from GPe and midbrain. Future studies are needed to unravel the intricate organization of these pathways in terms of pre- and postsynaptic cell types and to fully understand their role in striatal function and dysfunction.
Conflict of interest statement Nothing declared.
Acknowledgements We thank Sten Grillner, Andrew Sharott, and Natalie Doig for comments on early versions of the manuscript. This work was supported by the Medical Research Council UK, the European Research Council, the Knut & Alice Wallenberg Foundation, and the Karolinska Institutet Strategic research program in Neuroscience (StratNeuro).
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47. Moss J, Ungless MA, Bolam JP: Dopaminergic axons in different divisions of the adult rat striatal complex do not express vesicular glutamate transporters. Eur J Neurosci 2011, 33: 1205-1211. 48. Straub C, Tritsch NX, Hagan NA, Gu C, Sabatini BL: Multiphasic modulation of cholinergic interneurons by nigrostriatal afferents. J Neurosci 2014, 34:8557-8569. 49. Brown MT, Tan KR, O’Connor EC, Nikonenko I, Muller D, Luscher C: Ventral tegmental area GABA projections pause accumbal cholinergic interneurons to enhance associative learning. Nature 2012, 492:452-456. 50. Bevan MD, Booth PA, Eaton SA, Bolam JP: Selective innervation of neostriatal interneurons by a subclass of neuron in the globus pallidus of the rat. J Neurosci 1998, 18:9438-9452. 51. Kita H, Kitai ST: The morphology of globus pallidus projection neurons in the rat: an intracellular staining study. Brain Res 1994, 636:308-319. 52. Mallet N, Micklem BR, Henny P, Brown MT, Williams C, Bolam JP, Nakamura KC, Magill PJ: Dichotomous organization of the external globus pallidus. Neuron 2012, 74:1075-1086. This study described a novel type of pallidal neuron, characterized by ‘atypical’ spiking activity and extensive innervation of striatum, as revealed using juxtacellular recordings and staining. 53. Mastro KJ, Bouchard RS, Holt HA, Gittis AH: Transgenic mouse lines subdivide external segment of the globus pallidus (GPe) neurons and reveal distinct GPe output pathways. J Neurosci 2014, 34:2087-2099. 54. Dautan D, Huerta-Ocampo I, Witten IB, Deisseroth K, Bolam JP, Gerdjikov T, Mena-Segovia J: A major external source of cholinergic innervation of the striatum and nucleus accumbens originates in the brainstem. J Neurosci 2014, 34:4509-4518. Cholinergic synaptic transmission in the striatum was long believed to originate solely from striatal cholinergic interneurons. This study showed a novel cholinergic afferent input originating from the PPN and LDT. 55. Bolam JP, Pissadaki EK: Living on the edge with too many mouths to feed: why dopamine neurons die. Mov Disord 2012, 27:1478-1483. 56. Matsuda W, Furuta T, Nakamura KC, Hioki H, Fujiyama F, Arai R, Kaneko T: Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J Neurosci 2009, 29:444-453. 57. Moss J, Bolam JP: A dopaminergic axon lattice in the striatum and its relationship with cortical and thalamic terminals. J Neurosci 2008, 28:11221-11230. 58. Moss J, Bolam JP: The relationship between dopaminergic axons and glutamatergic synapses in the striatum: structural considerations. In Dopamine handbook. Edited by Iversen LL, Iversen SD, Dunnett SB, Bjo¨rklund A. Oxford University Press; 2010:49-59. 59. Reynolds JN, Wickens JR: Dopamine-dependent plasticity of corticostriatal synapses. Neural Netw 2002, 15:507-521. 60. Threlfell S, Lalic T, Platt NJ, Jennings KA, Deisseroth K, Cragg SJ: Striatal dopamine release is triggered by synchronized activity in cholinergic interneurons. Neuron 2012, 75:58-64. This study showed that dopamine release in the striatum can be evoked locally by synchronous activation of cholinergic interneurons. Such striatal release could be evoked by axo-axonic nicotinic excitation independently of action-potential discharge in somata of midbrain dopaminergic neurons. 61. Adler A, Katabi S, Finkes I, Prut Y, Bergman H: Different correlation patterns of cholinergic and GABAergic interneurons with striatal projection neurons. Front Syst Neurosci 2013, 7:47. 62. Raz A, Feingold A, Zelanskaya V, Vaadia E, Bergman H: Neuronal synchronization of tonically active neurons in the striatum of normal and parkinsonian primates. J Neurophysiol 1996, 76:2083-2088.
Current Opinion in Neurobiology 2015, 33:182–187
ScienceDirect Local and afferent synaptic pathways in the striatal microcircuitry Gilad Silberberg1 and J Paul Bolam2 The striatum is the largest structure of the basal ganglia, receiving synaptic input from multiple regions including the neocortex, thalamus, external globus pallidus, and midbrain. Earlier schemes of striatal connectivity presented a relatively simple architecture which included primarily excitatory input from the neocortex, dopaminergic input from the midbrain, and intrastriatal connectivity between projection neurons and a small number of interneuron types. In recent years this picture has changed, largely due to the introduction of new experimental methods to reveal cell types and their connectivity. The striatal microcircuit is now considered to consist of several newly defined neuron types which are intricately and selectively interconnected. New afferent pathways have been discovered, as well as novel properties of previously known afferents such as the midbrain dopaminergic inputs. In this review we aim to provide a summary of these recent discoveries. Addresses 1 Department of Neuroscience, Karolinska Institutet, Retzius va¨g 8, Stockholm 17177, Sweden 2 Medical Research Council Brain Network Dynamics Unit, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK Corresponding author: Silberberg, Gilad ([email protected])
Current Opinion in Neurobiology 2015, 33:182–187
nitric oxide synthase (NOS), neuropeptide-Y (NPY) and SOM, whereas others appeared to be mutually exclusive, as in the case of SOM and PV. The use of transgenic mice selectively expressing fluorescent markers under the control of promoters of specific markers has led to the identification of several classes of interneuron and enabled a systematic characterization of the various types, resulting in more refined classification schemes. Tyrosine hydroxylase-expressing interneurons
Using a BAC transgenic mouse expressing EGFP in tyrosine-hydroxylase (TH) expressing neurons (EGFPTH+), Ibanez-Sandoval and colleagues [3] defined four interneuron subtypes based on their electrophysiological properties. The interneurons are all GABAergic, most of which have novel intrinsic electrophysiological properties. TH was not co-expressed with NOS, PV, or calretinin, suggesting that this population of interneurons is indeed novel and not part of previously characterized groups. Interestingly, TH expression increased following midbrain 6-hydroxydopamine (6-OHDA) lesions, which could suggest a compensatory mechanism following dopamine depletion [4], however, the TH-expressing interneurons have been shown to release GABA but not dopamine [5] and thus represent populations of GABAergic neurons.
This review comes from a themed issue on Motor circuits and action Edited by Ole Kiehn and Mark Churchland
http://dx.doi.org/10.1016/j.conb.2015.05.002 0959-4388/# 2015 Elsevier Ltd. All rights reserved.
Striatal neuron types The striatum consists of a majority of projection neurons, the medium spiny neurons (MSNs) and a small, yet diverse population of interneurons. Interneurons were initially divided into four subtypes, including three types of GABAergic interneurons, and the tonically active cholinergic interneurons [1,2]. These electrophysiologically defined subtypes also fitted a molecular profile based on immunostaining for markers such as parvalbumin (PV), calretinin (CR), somatostatin (SOM), and choline-acetyltransferase (ChAT). Some of the markers used in the characterization of the neurons were co-localised such as Current Opinion in Neurobiology 2015, 33:182–187
NPY-expressing interneurons
Using a similar approach to that used in the discovery of TH-positive interneurons, the use of a transgenic GFPNPY reporter mouse line has revealed the existence of at least two distinct types of interneurons that express NPY [6]. One type was the previously described ‘low-threshold spiking’ (LTS) interneuron and the other was defined as ‘NPY-neurogliaform’ (NPY-NGF), based on its similarity to the cortical neurogliaform interneurons. The two NPYGFP interneurons exhibit different electrophysiological, morphological, molecular, and synaptic profiles, thus justifying the division into two distinct subtypes. One important feature of the NPY-LTS interneurons recorded in mouse striatum is their tonic activity [7], making them the second tonically active interneuron type in the striatal microcircuit in addition to cholinergic interneurons [8]. Interestingly, in rats, no NPY-NGF have been reported, and NPY interneurons expressing NOS do not display tonic discharge in vivo [9]. 5HT3a-expressing interneurons
Using BAC transgenic eGFP mouse lines, Fishell, Rudy, and colleagues have identified a population of neocortical www.sciencedirect.com
Synaptic pathways in the striatal microcircuitry Silberberg and Bolam 183
GABAergic interneurons that express the 5HT3a serotonin receptor [10,11]. In the neocortex, the 5HT3a-expressing neurons are prevalent in superficial cortical layers and together with the PV- and SOM-expressing interneurons, could account for almost all GABAergic interneurons. In the same mouse line 5HT3a-expressing interneurons were also characterized in the striatum, revealing a large and diverse population [12]. Similar to TH-expressing interneurons, striatal 5HT3a-EGFP interneurons exhibit distinct electrophysiological subtypes, as well as different co-expression patterns with PV, NOS, TH, and calretinin. The greatest degree of overlap was between 5HT3a and PV, which was also reflected in the fast-spiking electrophysiological phenotype of more than 30% of recorded 5HT3a-GFP interneurons. One subtype of 5HT3a interneuron was shown to be activated by nicotinic input from cholinergic interneurons and provides GABAergic input to MSNs [13]. Summary
The number of striatal neuron subtypes is larger than previously assumed and is likely to change in the coming years and vary according to different classification schemes used in the field. The classification is not always straightforward due to the overlap of the different molecular, electrophysiological, and morphological properties, as well as differences between species. New directions towards the resolution of cell type classification may now
be provided by single cell RNA sequencing [14] and fate mapping [15] studies, where the electrophysiological, morphological, and network properties of neurons are correlated to their developmental origin and molecular fingerprint.
Striatal interneuron connectivity Striatal interneurons of the different types are instrumental in sculpting striatal output via intrastriatal synaptic connections. Perhaps the most prominent of the intrastriatal synapses are the GABAergic synapses formed between FS interneurons and MSNs [16] (Figure 1). These synapses are characterized by a very high connection probability, with each FS interneuron contacting a majority of its neighboring (within 100 mm radius) MSNs [17]. A single FS-MSN IPSP is sufficient to alter the discharge pattern of the postsynaptic MSN [16,18]. The same presynaptic FS interneurons contact both direct and indirect pathway MSNs, with preference towards direct pathway (D1 expressing MSNs) [17,19], which is reversed following 6-OHDA induced dopamine depletion by selective increase in the connections onto D2 MSNs [20]. Striatal FS interneurons share many of the morphological, electrophysiological, and synaptic properties with cortical FS interneurons, however, one striking difference is the lack of reciprocity between them and their targeted projection neurons. In the neocortex there is a high degree of reciprocity between FS
Figure 1
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A selective ‘blanket’ of inhibition by striatal PV interneurons. (a) Schematic representation of an experiment showing robust inhibition of MSNs by optogenetic activation of fast-spiking PV-expressing interneurons and avoidance of a simultaneously recorded neighboring cholinergic interneuron (CHIN). (b) Blanket of feed-forward inhibition by PV interneurons onto MSNs, with ‘holes’ representing the avoided cholinergic interneurons.Adapted from [27,28]. www.sciencedirect.com
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184 Motor circuits and action
interneurons and pyramidal cells [21–25], whereas striatal FS interneurons strictly provide unidirectional ‘feed-forward’ inhibition of MSNs, with no report so far, of MSN to FS synaptic interactions [16,17,19,26]. In neocortex as well as striatum, FS interneurons appear to provide a so called ‘blanket’ of inhibition covering neighboring projection neurons [23,27]. However, this inhibitory blanket does not equally influence all types of neighboring neurons but rather displays selectivity in its targeting. In the striatum, PV interneurons selectively avoid cholinergic interneurons, while robustly inhibiting neighboring MSNs [28], thus exhibiting a high degree of selectivity in the local circuitry, similar to the local target preference found in neocortical interneurons [29] (Figure 1). Another source of inhibitory input to MSNs is indirectly evoked by striatal cholinergic interneurons. This class of neuron provides nicotine-receptor dependent disynaptic inhibition of both types of MSN upon synchronized activation [30] (Figure 2). The GABAergic response
of MSNs can be divided into two components based on the synaptic kinetics, in which the slow component (decay time constant of 80 ms) is mediated by NPYNGF interneurons (Figure 2). NPY-NGF interneurons receive direct nicotinic excitation from cholinergic interneurons and synchronous optogenetic activation of several cholinergic interneurons can evoke discharge that delivers the slow GABAA inhibition. Activation of cholinergic interneurons also results in a fast GABAA component which is likely to be mediated by axo-axonic activation of afferent midbrain axons [31] (see ‘Striatal afferents’ section).
Striatal afferents The striatum acts as a hub upon which numerous streams of information converge from different brain regions, mediated by different types of neurotransmitter. In recent years several new pathways have been discovered and characterized that are likely to have profound effects on the flow of information through the striatum (Figure 2). Glutamatergic afferents
Figure 2
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Afferent striatal pathways. Schematic of striatal afferents from GPe [52], PPN [54], and SNc [43,46]. Intrastriatal connections between NPY-NGF and 5HT3a interneurons, and cholinergic interneurons [30,42] underlying disynaptic pathways between cholinergic interneurons and MSNs [31,60]. The partial innervation of MSNs by afferent projections from GPe and SNc is made only for illustration purposes. Abbreviations: GPe, globus pallidus external segment; PPN, pedunculopontine nucleus; SNc, substantia nigra pars compacta; CHIN, cholinergic interneurons; MSN, medium spiny neurons; NPYNGF, neuropeptide-Y expressing neurogliaform interneurons; 5HT3a, 5-hydroxytryptamine 3a receptor expressing interneurons; PV, parvalbumin expressing interneurons; GP-TI, prototypic GPe neurons; GP-TA, atypical; arkypallidal GP neurons; Glu, glutamate; ACh, acetylcholine. Current Opinion in Neurobiology 2015, 33:182–187
Cortical input to striatum is widely considered to be the dominant driver of striatal activity, and an important aspect regarding this pathway is the target preference of cortical inputs onto different types of striatal neuron. Both direct and indirect pathway MSNs have been shown to receive cortical input, however it has been suggested that these inputs originate from different populations of cortical pyramidal neurons [32]. According to this view, direct pathway MSNs are preferentially targeted by ipsiand contralateral intra-telencephalic (IT) pyramidal neurons, whereas indirect pathway neurons are targeted by ipsilateral pyramidal tract (PT) neurons. This idea has been challenged in recent anatomical studies, where no significant difference was found in the cortical targeting of D1 and D2 MSNs [33,34]. Selective optogenetic activation of cortical afferents of IT and PT types showed that both direct and indirect pathway MSNs receive excitatory synaptic input from both corticostriatal pathways [35]. In vivo recordings of synaptic responses to sensory stimuli also do not support such an ipsilateral bias in cortical input to indirect pathway MSNs [36]. Striatal interneurons receive cortical input and display type-dependent response profiles to cortical as well as thalamic activity [9,37,38]. These differences in response profile may reflect the distinct membrane properties of the target interneurons [39] as well as differences in corticostriatal synaptic properties [40]. Glutamatergic input from thalamus also targets both direct and indirect pathway MSNs [33,41], converging with cortical input even at the single cell level [42]. In addition to the glutamatergic input from cortex and thalamus there is recent evidence in transgenic mouse lines for glutamate co-release from midbrain dopaminergic axons [43–45,46]. Such glutamate responses were www.sciencedirect.com
Synaptic pathways in the striatal microcircuitry Silberberg and Bolam 185
evoked in mouse striatum following optogenetic stimulation of dopamine axon terminals in both types of MSNs [46] as well as FS and cholinergic interneurons [43]. In adult rats, however, there is no expression of vesicular glutamate transporters in dopamine axon terminals in the dorsal or ventral striatum [47]. GABAergic afferents
The striatum consists of almost entirely GABAergic neurons, however, it also receives GABAergic afferent inputs. One source of striatal GABA is the midbrain (VTA and SNc), containing dopaminergic and GABAergic afferents. GABA has been shown to be co-released with dopamine onto both types of MSN [46] as well as cholinergic interneurons [43,48]. The striatum also receives GABAergic afferents from the midbrain that appear to target primarily cholinergic interneurons [49]. An additional source of afferent GABAergic input to the striatum originates in the external segment of the globus pallidus (GPe). Two subclasses of GABAergic neurons provide the innervation [50,51,52,53]. One type provides a fairly restricted innervation of the striatum and also innervates all caudal targets of the GPe in the basal ganglia; this type selectively targets striatal interneurons (Bevan et al., 1998). The second type, referred to as arkypallidal neurons, exclusively innervates the striatum and targets both types of MSN and interneurons [52]. Individual arkypallidal neurons give rise to as many as 13,000 synapses in the striatum and they have different electrophysiological and molecular profiles from other GPe neurons [15,52]. Cholinergic innervation of the striatum
The striatum contains some of the highest density of cholinergic markers in the brain and the only source of acetylcholine (ACh) was considered, for a long period, to be the cholinergic interneurons. However, a recent study in ChAT-cre rats, described a prominent afferent cholinergic pathway from the pedunculopontine nucleus (PPN) and the laterodorsal tegmentum (LDT) [54]. All striatal regions receive input from the PPN/LDT following a topographic organization in which dorsolateral striatum is targeted by rostral PPN and the medial and ventral striatum by LDT. The cholinergic terminals target both MSNs and interneurons, however the subtype of postsynaptic neurons is still unclear. Interestingly, cholinergic afferents from PPN appear to avoid striosomes, as revealed by mu-opioid receptor staining. Further research is required in order to determine the functional properties of the PPN cholinergic input and its interplay with striatal cholinergic interneurons. Dopamine
The striatum receives massive dopamine (DA) input from the midbrain, with individual midbrain neurons innervating large fractions of the striatum and giving rise to www.sciencedirect.com
hundreds of thousands of boutons [55–58]. DA release shapes the functional properties of striatal afferents, in particular the corticostriatal pathway [59]. Local THexpressing interneurons [45] have been shown not to release DA thus the only source of striatal DA is the axons of midbrain dopaminergic neurons. Optogenetic activation of cholinergic axons in the striatum induces release of DA in the striatum via axo-axonal interactions [60] (Figure 2). The ACh-dependent release of DA could be evoked independently of somatic discharge of the presynaptic midbrain neurons and was also triggered by activation of thalamic inputs to cholinergic interneurons. The interplay between afferent or locally induced DA release is still unclear. Local DA release largely depends on synchronous activation of cholinergic neurons and is not detected by activation of single interneurons [60]. It remains to be seen whether such a degree of synchrony emerges between cholinergic interneurons under physiological conditions. Combining the discovery of local DA release by optogenetic activation of cholinergic interneurons and the corelease of GABA by DA axons, it was then suggested that disynaptic inhibition observed between cholinergic interneurons and MSNs [30] is mediated by axo-axonic activation of DA terminals [31]. As shown earlier [30], optogenetic stimulation of cholinergic interneurons induced GABAergic responses in MSNs, that persists even in the presence of tetrodotoxin (TTX) and 4 aminopyridine (4AP), indicating an axo-axonic mechanism that is independent of action potential discharge in an intermediate GABAergic interneuron. The disynaptic inhibition was reduced following 6-OHDA lesions of the medial forebrain bundle further suggesting that it was mediated by midbrain DA axons. Interestingly, despite the observed disynaptic interactions between cholinergic interneurons and MSNs, no cross correlations in their spiking activity have been detected in awake behaving monkeys [61]. This apparent discrepancy raises the possibility that these disynaptic interactions are less common in vivo and may be activated only in particular epochs in which the synchrony of cholinergic interneurons is higher than normal [62]. Summary
The striatum is the largest nucleus of the basal ganglia, acting as a ‘hub’ onto which multiple input streams converge to interact with the intrastriatal network. The intricate connectivity patterns of the intrastriatal and afferent synapses are essential for proper function of the basal ganglia, and deviations from these patterns might lead to devastating motor and cognitive dysfunctions. The striatal microcircuitry, although comprised almost entirely by GABAergic neurons, also receives GABAergic input from several afferent pathways. In this review we aimed to highlight recent discoveries pertaining to intrastriatal and afferent synaptic Current Opinion in Neurobiology 2015, 33:182–187
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pathways, including GABAergic input from GPe and midbrain. Future studies are needed to unravel the intricate organization of these pathways in terms of pre- and postsynaptic cell types and to fully understand their role in striatal function and dysfunction.
Conflict of interest statement Nothing declared.
Acknowledgements We thank Sten Grillner, Andrew Sharott, and Natalie Doig for comments on early versions of the manuscript. This work was supported by the Medical Research Council UK, the European Research Council, the Knut & Alice Wallenberg Foundation, and the Karolinska Institutet Strategic research program in Neuroscience (StratNeuro).
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