Striatal Fast-spiking Interneurons Research Articles

Striatal cholinergic neurotransmission requires VGLUT3.

It is now clear that many neuronal populations release more than one classical neurotransmitter, yet in most cases the functional role of corelease is unknown. Striatal cholinergic interneurons release both glutamate and acetylcholine, and vesicular loading of glutamate has been shown to enhance acetylcholine content. Using a combination of optogenetics and whole-cell recordings in mice, we now provide physiological evidence that optogenetic stimulation of cholinergic interneurons triggers monosynaptic glutamate- and acetylcholine-mediated currents in striatal fast-spiking interneurons (FSIs), both of which depend on the expression of the vesicular glutamate transporter 3 (VGLUT3). In contrast to corticostriatal glutamatergic inputs onto FSIs, which are mediated primarily by AMPA-type glutamate receptors, glutamate release by cholinergic interneurons activates both AMPA- and NMDA-type glutamate receptors, suggesting a unique role for these inputs in the modulation of FSI activity. Importantly, we find that the loss of VGLUT3 not only markedly attenuates glutamatergic and cholinergic inputs on FSIs, but also significantly decreases disynaptic GABAergic input onto medium spiny neurons (MSNs), the major output neurons of the striatum. Our data demonstrate that VGLUT3 is required for normal cholinergic signaling onto FSIs, as well as for acetylcholine-dependent disynaptic inhibition of MSNs. Thus, by supporting fast glutamatergic transmission as well as by modulating the strength of cholinergic signaling, VGLUT3 has the capacity to exert widespread influence on the striatal network.

Striatal Cholinergic Interneurons Drive GABA Release from Dopamine Terminals

Striatal cholinergic interneurons are implicated in motor control, associative plasticity, and reward-dependent learning. Synchronous activation of cholinergic interneurons triggers large inhibitory synaptic currents in dorsal striatal projection neurons, providing one potential substrate for control of striatal output, but the mechanism for these GABAergic currents is not fully understood. Using optogenetics and whole-cell recordings in brain slices, we find that a large component of these inhibitory responses derive from action-potential-independent disynaptic neurotransmission mediated by nicotinic receptors. Cholinergically driven IPSCs were not affected by ablation of striatal fast-spiking interneurons but were greatly reduced after acute treatment with vesicular monoamine transport inhibitors or selective destruction of dopamine terminals with 6-hydroxydopamine, indicating that GABA release originated from dopamine terminals. These results delineate a mechanism in which striatal cholinergic interneurons can co-opt dopamine terminals to drive GABA release and rapidly inhibit striatal output neurons.

Differential Entrainment and Learning-Related Dynamics of Spike and Local Field Potential Activity in the Sensorimotor and Associative Striatum

Parallel cortico-basal ganglia loops are thought to have distinct but interacting functions in motor learning and habit formation. In rats, the striatal projection neuron populations (MSNs) in the dorsolateral and dorsomedial striatum, respectively corresponding to sensorimotor and associative regions of the striatum, exhibit contrasting dynamics as rats acquire T-maze tasks (Thorn et al., 2010). Here, we asked whether these patterns could be related to the activity of local interneuron populations in the striatum and to the local field potential activity recorded simultaneously in the corresponding regions. We found that dorsolateral and dorsomedial striatal fast-spiking interneurons exhibited task-specific and training-related dynamics consistent with those of corresponding MSN populations. Moreover, both MSNs and interneuron populations in both regions became entrained to theta-band (5-12 Hz) frequencies during task acquisition. However, the predominant entrainment frequencies were different for the sensorimotor and associative zones. Dorsolateral striatal neurons became entrained mid-task to oscillations centered ∼ 5 Hz, whereas simultaneously recorded neurons in the dorsomedial region became entrained to higher frequency (∼ 10 Hz) rhythms. These region-specific patterns of entrainment evolved dynamically with the development of region-specific patterns of interneuron and MSN activity, indicating that, with learning, these two striatal regions can develop different frequency-modulated circuit activities in parallel. We suggest that such differential entrainment of sensorimotor and associative neuronal populations, acquired through learning, could be critical for coordinating information flow throughout each trans-striatal network while simultaneously enabling nearby components of the separate networks to operate independently.

Parvalbumin Tunes Spike-Timing and Efferent Short-Term Plasticity in Striatal Fast Spiking Interneurons

Striatal fast spiking interneurons (FSI) modulate the output of the striatum by synchronizing medium-sized spiny neurons (MSN). FSI are the only striatal neurons to express the calcium-binding protein parvalbumin (PV). This selective expression of PV raises questions about the functional role of this calcium buffer in controlling FSI calcium dynamics, and, consequently, the FSI spiking mode and neurotransmission. To study the functional involvement of FSI in striatal microcircuit activity and the role of PV in FSI function, we performed perforated patch recordings on EGFP-expressing FSI in brain slices from control and PV-/- mice. Our results revealed that PV-/- FSI fired more regularly and were more excitable than control FSI by a mechanism in which calcium buffering is linked to spiking activity as the result of the activation of small conductance (SK) calcium-dependent potassium channels. A modeling approach of striatal FSI supports our experimental results. Furthermore, PV deletion modified frequency-specific short-term plasticity at inhibitory FSI to MSN synapses. Our results therefore support the hypothesis that in FSI, PV is crucial for the fine-tuning of the temporal responses of the FSI network and for the orchestration of MSN populations. This, in turn, may play a direct role in the generation and pathology-related worsening of motor rhythms.

Distinct Target Selectivity of Fast-Spiking Interneurons in the Regulation of Striatal Output Pathways

The striatum is the main input nucleus of the basal ganglia. It receives excitatory inputs from the cortex and the thalamus that predominantly target the medium-sized spiny neurons (MSNs), the main neuronal cell-type and the projection neurons of the striatum. MSNs are divided in two subpopulations. A simplified model of the basal ganglia circuit proposes that the so-called “direct pathway” facilitates movements via the dMSNs, while the so-called “indirect pathway” terminates or suppresses movements via the iMSNs. Imbalances in the activity of both pathways are thought to have an effect on numerous movement disorders. Therefore, the output of the striatum is dependent upon which MSN type is stimulated, but also on their respective firing rate. These firing rates are themselves controlled by feedforward inhibition from local interneurons which is largely mediated by parvalbumin (PV)-expressing fast-spiking interneurons (FSIs). They inhibit to both direct and indirect pathway MSNs and are also interconnected with each other via electrical and chemical synapses. In order to understand how activity is regulated within the striatum, it is essential to understand the functional connectivity between the different neuronal types. Further, it is relevant to know whether feedforward inhibition differentially affect MSNs in the direct or indirect pathway. In this study we focus on the GABAergic microcircuits of the mouse striatum by investigating the target selectivity of striatal FSIs using optogenetic techniques, which enable us to selectively stimulate FSIs using pulses of 470 nm blue light. This approach is also combined with electrophysiological measurements using patch clamp recordings in acute brain slices. The inhibitory post-synaptic currents of both subpopulations of MSNs due to striatal microcircuitry FSI activation are compared in physiological and pathological models of chronic amphetamine/cocaine administration.

Effect of gap junctions on the firing patterns and synchrony for different external inputs in the striatal fast-spiking neuron network.

Gap junctions are the mechanism for striatal fast-spiking interneurons (FSIs) to interconnect with each other and play an important role in determining the physiological functioning of the FSIs. To investigate the effect of gap junctions on the firing activities and synchronization of the network for different external inputs, a simple network with least connections and a Newman-Watts small-world network were constructed. Our research shows that both properties of neural networks are related to the conductance of the gap junctions, as well as the frequency and correlation of the external inputs. The effect of gap junctions on the synchronization of network is different for inputs with different frequencies and correlations. The addition of gap junctions can promote the network synchrony in some conditions but suppress it in others, and they can inhibit the firing activities in most cases. Both the firing rate and synchronization of the network increase along with the increase of the electrical coupling strength for inputs with low frequency and high correlation. Thus, the network of coupled FSIs can act as a detector for synchronous synaptic input from cortex and thalamus.

Parvalbumin tunes spike‐timing and efferent short‐term plasticity in striatal fast spiking interneurons

Striatal fast spiking interneurons (FSIs) modulate output of the striatum by synchronizing medium-sized spiny neurons (MSNs). Recent studies have broadened our understanding of FSIs, showing that they are implicated in severe motor disorders such as parkinsonism, dystonia and Tourette syndrome. FSIs are the only striatal neurons to express the calcium-binding protein parvalbumin (PV). This selective expression of PV raises questions about the functional role of this Ca(2+) buffer in controlling FSI Ca(2+) dynamics and, consequently, FSI spiking mode and neurotransmission. To study the functional involvement of FSIs in striatal microcircuit activity and the role of PV in FSI function, we performed perforated patch recordings on enhanced green fluorescent protein-expressing FSIs in brain slices from control and PV-/- mice. Our results revealed that PV-/- FSIs fired more regularly and were more excitable than control FSIs by a mechanism in which Ca(2+) buffering is linked to spiking activity as a result of the activation of small conductance Ca(2+)-dependent K(+) channels. A modelling approach of striatal FSIs supports our experimental results. Furthermore, PV deletion modified frequency-specific short-term plasticity at inhibitory FSI to MSN synapses. Our results therefore reinforce the hypothesis that in FSIs, PV is crucial for fine-tuning of the temporal responses of the FSI network and for the orchestration of MSN populations. This, in turn, may play a direct role in the generation and pathology-related worsening of motor rhythms.

Target Selectivity of Feedforward Inhibition by Striatal Fast-Spiking Interneurons

The striatal microcircuitry consists of a vast majority of projection neurons, the medium spiny neurons (MSNs), and a small yet diverse population of interneurons. To understand how activity is orchestrated within the striatum, it is essential to unravel the functional connectivity between the different neuronal types. Fast-spiking (FS) interneurons provide feedforward inhibition to both direct and indirect pathway MSNs and are important in sculpting their output to downstream basal ganglia nuclei. FS interneurons are also interconnected with each other via electrical and chemical synapses; however, whether and how they inhibit other striatal interneuron types remains unknown. In this study we combined multineuron whole-cell recordings with optogenetics to determine the target selectivity of feedforward inhibition by striatal FS interneurons. Using transgenic and viral approaches we directed expression of channelrhodopsin 2 (ChR2) to FS interneurons to study their connectivity within the mouse striatal microcircuit. Optogenetic stimulation of ChR2-expressing FS interneurons generated strong and reliable GABA(A)-dependent synaptic inputs in MSNs. In sharp contrast, simultaneously recorded neighboring cholinergic interneurons did not receive any synaptic inputs from photostimulated FS cells, and a minority of low-threshold spiking (LTS) interneurons responded weakly. We further tested the synaptic connectivity between FS and LTS interneurons using paired recordings, which showed only sparse connectivity. Our results show that striatal FS interneurons form a feedforward inhibitory circuit that is target selective, inhibiting projection neurons while avoiding cholinergic interneurons and sparsely contacting LTS interneurons, thus supporting independent modulation of MSN activity by the different types of striatal interneurons.

Dynamics of action potential firing in electrically connected striatal fast-spiking interneurons

Fast-spiking interneurons (FSIs) play a central role in organizing the output of striatal neural circuits, yet functional interactions between these cells are still largely unknown. Here we investigated the interplay of action potential (AP) firing between electrically connected pairs of identified FSIs in mouse striatal slices. In addition to a loose coordination of firing activity mediated by membrane potential coupling, gap junctions (GJ) induced a frequency-dependent inhibition of spike discharge in coupled cells. At relatively low firing rates (2–20 Hz), some APs were tightly synchronized whereas others were inhibited. However, burst firing at intermediate frequencies (25–60 Hz) mostly induced spike inhibition, while at frequencies >50–60 Hz FSI pairs tended to synchronize. Spike silencing occurred even in the absence of GABAergic synapses or persisted after a complete block of GABAA receptors. Pharmacological suppression of presynaptic spike afterhyperpolarization (AHP) caused postsynaptic spikelets to become more prone to trigger spikes at near-threshold potentials, leading to a mostly synchronous firing activity. The complex pattern of functional coordination mediated by GJ endows FSIs with peculiar dynamic properties that may be critical in controlling striatal-dependent behavior.

Control of Neuronal Excitability by Calcium Binding Proteins: A New Mathematical Model for Striatal Fast-Spiking Interneurons

Calcium binding proteins, such as parvalbumin (PV), are abundantly expressed in distinctive patterns in the central nervous system but their physiological function remains poorly understood. Notably, at the level of the striatum, where PV is only expressed in the fast-spiking (FS) interneurons. FS interneurons form an inhibitory network modulating the output of the striatum by synchronizing medium-sized spiny neurons (MSN). So far the existing conductance-based computational models for FS neurons did not allow the study of the coupling between PV concentration and electrical activity. In the present paper, we propose a new mathematical model for the striatal FS interneurons that includes apamin-sensitive small conductance Ca2+-dependent K+ channels (SK) and the presence of a calcium buffer. Our results show that a variation in the concentration of PV can modulate substantially the intrinsic excitability of the FS interneurons and therefore may be involved in the information processing at the striatal level.

Control of neuronal excitability by calcium binding proteins : a new mathematical model for striatal fast-spiking interneurons

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Selective Inhibition of Striatal Fast-Spiking Interneurons Causes Dyskinesias

Fast-spiking interneurons (FSIs) can exert powerful control over striatal output, and deficits in this cell population have been observed in human patients with Tourette syndrome and rodent models of dystonia. However, a direct experimental test of striatal FSI involvement in motor control has never been performed. We applied a novel pharmacological approach to examine the behavioral consequences of selective FSI suppression in mouse striatum. IEM-1460, an inhibitor of GluA2-lacking AMPARs, selectively blocked synaptic excitation of FSIs but not striatal projection neurons. Infusion of IEM-1460 into the sensorimotor striatum reduced the firing rate of FSIs but not other cell populations, and elicited robust dystonia-like impairments. These results provide direct evidence that hypofunction of striatal FSIs can produce movement abnormalities, and suggest that they may represent a novel therapeutic target for the treatment of hyperkinetic movement disorders.

Rapid Target-Specific Remodeling of Fast-Spiking Inhibitory Circuits after Loss of Dopamine

In Parkinson's disease (PD), dopamine depletion alters neuronal activity in the direct and indirect pathways and leads to increased synchrony in the basal ganglia network. However, the origins of thesechanges remain elusive. Because GABAergic interneurons regulate activity of projection neurons andpromote neuronal synchrony, we recorded from pairs of striatal fast-spiking (FS) interneurons and direct- or indirect-pathway MSNs after dopamine depletion with 6-OHDA. Synaptic properties ofFS-MSN connections remained similar, yet within 3days of dopamine depletion, individual FS cells doubled their connectivity to indirect-pathway MSNs, whereas connections to direct-pathway MSNs remained unchanged. A model of the striatal microcircuit revealed that such increases in FS innervation were effective at enhancing synchrony within targeted cell populations. These data suggest that after dopamine depletion, rapid target-specific microcircuit organization in the striatum may lead to increased synchrony of indirect-pathway MSNs that contributes to pathological network oscillations and motor symptoms of PD.

Plastic Changes in Striatal Fast-Spiking Interneurons Following Hemicerebellectomy and Environmental Enrichment

Recent findings suggest marked interconnections between the cerebellum and striatum, thus challenging the classical view of their segregated operation in motor control. Therefore, this study was aimed at further investigating this issue by analyzing the effects of hemicerebellectomy (HCb) on density and dendritic length of striatal fast-spiking interneurons (FSi). First, we analyzed the plastic rearrangements of striatal FSi morphology in hemicerebellectomized animals reared in standard conditions. Then, since environmental enrichment (EE) induces structural changes in experimental models of brain disease, we evaluated FSi morphology in lesioned animals exposed to an enriched environment after HCb. Although HCb did not affect FSi density, it progressively shrank dendritic branching of striatal FSi of both sides. These plastic changes, already evident 15days after the cerebellar ablation, became very marked 30days after the lesion. Such a relevant effect was completely abolished by postoperative enrichment. EE not only counteracted shrinkage of FSi dendritic arborization but also provoked a progressive increase in dendritic length which surpassed that of the controls as the enrichment period lengthened. These data confirm that the cerebellum and striatum are more interconnected than previously retained. Furthermore, cerebellar damage likely evokes a striatal response through cortical mediation. The EE probably modifies HCb-induced plastic changes in the striatum by increasing the efficiency of the cortical circuitry. This is the first study describing the morphological rearrangement of striatal FSi following a cerebellar lesion; it provides the basis for further studies aimed at investigating the mechanisms underlying cerebello-striatal "talking."

Functional properties of striatal fast-spiking interneurons.

Striatal fast-spiking interneurons (FSIs) have a major influence over behavioral output, and a deficit in these cells has been observed in dystonia and Tourette syndrome. FSIs receive cortical input, are coupled together by gap junctions, and make perisomatic GABAergic synapses onto many nearby projection neurons. Despite being critical components of striatal microcircuits, until recently little was known about FSI activity in behaving animals. Striatal FSIs are near-continuously active in awake rodents, but even neighboring FSIs show uncorrelated activity most of the time. A coordinated “pulse” of increased FSI firing occurs throughout striatum when rats initiate one chosen action while suppressing a highly trained alternative. This pulse coincides with a drop in globus pallidus population activity, suggesting that pallidostriatal disinhibition may have a important role in timing or coordinating action execution. In addition to changes in firing rate, FSIs show behavior-linked modulation of spike timing. The variability of inter-spike intervals decreases markedly following instruction cues, and FSIs also participate in fast striatal oscillations that are linked to rewarding events and dopaminergic drugs. These studies have revealed novel and unexpected properties of FSIs, that should help inform new models of striatal information processing in both normal and aberrant conditions.

Striatal Fast-Spiking Interneurons: From Firing Patterns to Postsynaptic Impact

In the striatal microcircuit, fast-spiking (FS) interneurons have an important role in mediating inhibition onto neighboring medium spiny (MS) projection neurons. In this study, we combined computational modeling with in vitro and in vivo electrophysiological measurements to investigate FS cells in terms of their discharge properties and their synaptic efficacies onto MS neurons. In vivo firing of striatal FS interneurons is characterized by a high firing variability. It is not known, however, if this variability results from the input that FS cells receive, or if it is promoted by the stuttering spike behavior of these neurons. Both our model and measurements in vitro show that FS neurons that exhibit random stuttering discharge in response to steady depolarization do not show the typical stuttering behavior when they receive fluctuating input. Importantly, our model predicts that electrically coupled FS cells show substantial spike synchronization only when they are in the stuttering regime. Therefore, together with the lack of synchronized firing of striatal FS interneurons that has been reported in vivo, these results suggest that neighboring FS neurons are not in the stuttering regime simultaneously and that in vivo FS firing variability is more likely determined by the input fluctuations. Furthermore, the variability in FS firing is translated to variability in the postsynaptic amplitudes in MS neurons due to the strong synaptic depression of the FS-to-MS synapse. Our results support the idea that these synapses operate over a wide range from strongly depressed to almost fully recovered. The strong inhibitory effects that FS cells can impose on their postsynaptic targets, and the fact that the FS-to-MS synapse model showed substantial depression over extended periods of time might indicate the importance of cooperative effects of multiple presynaptic FS interneurons and the precise orchestration of their activity.

Selective Activation of Striatal Fast-Spiking Interneurons during Choice Execution

Basal ganglia circuits are essential for the organization and execution of voluntary actions. Within the striatum, fast-spiking interneurons (FSIs) are thought to tightly regulate the activity of medium-spiny projection neurons (MSNs) through feed-forward inhibition, yet few studies have investigated the functional contributions of FSIs in behaving animals. We recorded presumed MSNs and FSIs together with motor cortex and globus pallidus (GP) neurons, in rats performing a simple choice task. MSN activity was widely distributed across the task sequence, especially near reward receipt. By contrast, FSIs showed a coordinated pulse of increased activity as chosen actions were initiated, in conjunction with a sharp decrease in GP activity. Both MSNs and FSIs were direction selective, but neighboring MSNs and FSIs showed opposite selectivity. Our findings suggest that individual FSIs participate in local striatal information processing, but more global disinhibition of FSIs by GP is important for initiating chosen actions while suppressing unwanted alternatives.

Fast‐spiking interneurons of the rat ventral striatum: temporal coordination of activity with principal cells and responsiveness to reward

Although previous in vitro studies revealed inhibitory synaptic connections of fast-spiking interneurons to principal cells in the striatum, uncertainty remains about the nature of the behavioural events that correlate with changes in interneuron activity and about the temporal coordination of interneuron firing with spiking of principal cells under natural conditions. Using in vivo tetrode recordings from the ventral striatum in freely moving rats, fast-spiking neurons were distinguished from putative medium-sized spiny neurons on the basis of their spike waveforms and rates. Cross-correlograms of fast-spiking and putative medium-sized spiny neuron firing patterns revealed a variety of temporal relationships, including peaks of concurrent firing and transient decrements in medium-sized spiny neuron spiking around fast-spiking unit activity. Notably, the onset of these decrements was mostly in advance of the fast-spiking unit firing. Many of these temporal relationships were dependent on the sleep-wake state. Coordinated activity was also found amongst pairs of the same phenotype, both fast-spiking units and putative medium-sized spiny neurons, which was often marked by a broad peak of concurrent firing. When studying fast-spiking neurons in a reward-searching task, they generally showed a pre-reward ramping increment in firing rate but a decrement specifically when the rat received reward. In conclusion, our data indicate that various forms of temporally coordinated activity exist amongst ventral striatal interneurons and principal cells, which cannot be explained by feed-forward inhibitory circuits alone. Furthermore, firing patterns of ventral striatal fast-spiking interneurons do not merely correlate with the general arousal state of the animal but display distinct reward-related changes in firing rate.

Local dynamics of gap-junction-coupled interneuron networks

Interneurons coupled by both electrical gap-junctions (GJs) and chemical GABAergic synapses are major components of forebrain networks. However, their contributions to the generation of specific activity patterns, and their overall contributions to network function, remain poorly understood. Here we demonstrate, using computational methods, that the topological properties of interneuron networks can elicit a wide range of activity dynamics, and either prevent or permit local pattern formation. We systematically varied the topology of GJ and inhibitory chemical synapses within simulated networks, by changing connection types from local to random, and changing the total number of connections. As previously observed we found that randomly coupled GJs lead to globally synchronous activity. In contrast, we found that local GJ connectivity may govern the formation of highly spatially heterogeneous activity states. These states are inherently temporally unstable when the input is uniformly random, but can rapidly stabilize when the network detects correlations or asymmetries in the inputs. We show a correspondence between this feature of network activity and experimental observations of transient stabilization of striatal fast-spiking interneurons (FSIs), in electrophysiological recordings from rats performing a simple decision-making task. We suggest that local GJ coupling enables an active search-and-select function of striatal FSIs, which contributes to the overall role of cortical-basal ganglia circuits in decision-making.

Opposite Effects of Stimulant and Antipsychotic Drugs on Striatal Fast-Spiking Interneurons

Psychomotor stimulants and typical antipsychotic drugs have powerful but opposite effects on mood and behavior, largely through alterations in striatal dopamine signaling. Exactly how these drug actions lead to behavioral change is not well understood, as previous electrophysiological studies have found highly heterogeneous changes in striatal neuron firing. In this study, we examined whether part of this heterogeneity reflects the mixture of distinct cell types present in the striatum, by distinguishing between medium spiny projection neurons (MSNs) and presumed fast-spiking interneurons (FSIs), in freely moving rats. The response of MSNs to both the stimulant amphetamine (0.5 or 2.5 mg/kg) and the antipsychotic eticlopride (0.2 or 1.0 mg/kg) remained highly heterogeneous, with each drug causing both increases and decreases in the firing rate of many MSNs. By contrast, FSIs showed a far more uniform, dose-dependent response to both drugs. All FSIs had decreased firing rate after high eticlopride. After high amphetamine most FSIs increased firing rate, and none decreased. In addition, the activity of the FSI population was positively correlated with locomotor activity, whereas the MSN population showed no consistent response. Our results show a direct relationship between the psychomotor effects of dopaminergic drugs and the firing rate of a specific striatal cell population. Striatal FSIs may have an important role in the behavioral effects of these drugs, and thus may be a valuable target in the development of novel therapies.