Functional diversity and specificity of neostriatal interneurons

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The firing of neostriatal spiny neurons in response to an excitatory input is modulated and sculpted by a variety of factors. Neostriatal interneurons are phenotypically diverse and have properties that enable them to specifically, but differentially, influence the activity of spiny neurons. Each of the three types of GABAergic interneurons produces a strong inhibitory postsynaptic potential in spiny neurons, the function of which is probably to influence the precise timing of action potential firing in either individual or ensembles of spiny neurons. By contrast, the role of cholinergic interneurons is to modulate the sub- and supra-threshold responses of spiny neurons to cortical and/or thalamic excitation, particularly in reward-related activities. Both classes of interneurons are important sites of action of neuromodulators in neostriatum, and act in different but complementary ways to modify the activity of the spiny projection neurons.

Introduction

The neostriatum (caudate-putamen) is the major division of the basal ganglia; it receives the majority of afferent input and is arguably the principal site within the basal ganglia where information processing occurs. The neostriatum receives input from the whole of the cortical mantle. The corticostriatal axons mainly innervate the GABAergic (γ-aminobutyric acid) medium-sized densely spiny neurons (MSNs), which account for the large majority of neostriatal neurons. These MSNs, in turn, project preferentially to the output nuclei of the basal ganglia or to the external segment of the globus pallidus (GPe) and thence to the output nuclei. Under resting conditions MSNs are hyperpolarized and silent. Increased activity of many convergent corticostriatal neurons (and possibly thalamostriatal neurons as well) depolarizes MSNs to the ‘up state’, from which additional excitatory inputs, an alteration in the strength of the synapses or an alteration in the balance of excitatory and inhibitory inputs leads to the firing of action potentials [1]. This phasic activity of the MSNs leads to altered rates and patterns of firing in the output nuclei through the ‘direct’ route and the ‘indirect’ route, which includes the GPe and subthalamic nucleus, and hence the targets of the basal ganglia. Although there are other routes by which extrinsic information reaches the basal ganglia (most notably through the corticosubthalamic pathway) it is clear that the response of MSNs to cortical and other inputs is the very essence of what the basal ganglia do.

The activity of individual and ensembles of MSNs is not solely dependent upon excitatory input but also on other factors, including dopaminergic and cholinergic neuromodulation and GABAergic inhibition from the local axon collaterals of MSNs and neostriatal interneurons (for recent review see Bolam et al. [2]). Neostriatal interneurons, which account for only a small proportion of all neostriatal neurons (2–3% in rodent [3•] and possibly up to 23% in primates [4]), are phenotypically diverse and highly specific in their properties enabling them to modulate and sculpt the response of MSNs to cortical input.

Section snippets

GABAergic interneurons

There are three subtypes of GABAergic interneurons in the neostriatum that can be distinguished neurochemically. One expresses the peptides somatostatin and neuropeptide Y (NPY) as well as the enzymes NADPH diaphorase and nitric oxide synthase. The other two express the calcium binding proteins parvalbumin or calretinin [5]. Together, the GABAergic interneurons comprise about 2% of the total neostriatal cell population [3•].

Parvalbumin interneurons

The best characterized GABAergic interneurons are those that express parvalbumin. On the basis of their electrophysiological properties they are referred to as fast-spiking (FS) interneurons [6]. Their somata average 16–18 μm in diameter and issue aspiny dendrites that branch modestly. There is some morphological heterogeneity, with one subtype exhibiting a relatively restricted and varicose dendritic arborization in the region of 200–300 μm in diameter, and the other displaying a more extended

Neuropeptide Y, nitric oxide synthase and somatostatin interneurons

A second neostriatal GABAergic interneuron was distinguished by the absence of parvalbumin but the presence of NPY, somatostatin, nitric oxide synthase and NADPH diaphorase 25., 26.. These medium sized neurons comprise 0.8% of neostriatal cells in rats [3•] and have the least dense axonal arborization of any of the neostriatal interneurons [6]. The neurons receive both cholinergic and dopaminergic input [9] and are characterized electrophysiologically by low threshold calcium spikes (LTS) and a

Calretinin interneurons

The third GABAergic interneuron colocalizes the calcium binding protein calretinin. These neurons make up 0.8% of neostriatal neurons in rats [3•]. They are of medium size, possess few, aspiny, infrequently branching dendrites and are relatively sparse in the caudal aspects of the neostriatum [28]. There are no electrophysiological data from intracellularly labeled cells identified as calretinin-positive, thus their electrophysiological profile remains unknown. However, in whole cell

Functional roles of neostriatal GABAergic interneurons

Each of the neostriatal GABAergic interneurons potently and monosynaptically inhibits MSNs, producing large IPSPs and/or IPSCs recordable at the soma (Figure 2). Given the differences in the physiology of the interneurons, it is likely that each subserves a slightly different role. By contrast, although the intrinsic mechanisms differ, each of the defined physiological subtypes can fire short bursts of action potentials that lead to fast and powerful suppression of spiking in MSNs. Thus, it now

Cholinergic interneurons

The largest neurons in the neostriatum, with a somatic diameter that can be in excess of 40 μm, are the giant aspiny neurons. They were first identified as interneurons by Kölliker (see [32] for discussion of Kölliker's work), and are now known to be cholinergic interneurons on the basis of choline acetyltransferase immunolabeling [33]. They comprise only ∼0.3% of the neurons in the rat neostriatum [3•], although, similar to the GABAergic interneurons they are likely to be present in greater

Functional role of the cholinergic interneurons

In primates, TANs were initially shown to respond to reward [40]. Subsequently, they were shown to acquire a stereotypical, synchronous pause of ∼200 ms in their activity in response to visual or auditory cues that predict saliency or reward in operant tasks [41]. These responses are crucially dependent upon input from both the nigrostriatal dopaminergic projections and the thalamostriatal projections, as the pause response disappears if either pathway is interrupted 36.•, 42.. These responses

Interneurons as sites of action of neuromodulators

GABAergic and cholinergic interneurons comprise an important locus of action for the neurotransmitters and/or neuromodulators, dopamine and acetylcholine in the neostriatum 47.•, 48., 49.•. Dopamine and acetylcholine do not produce frank excitation or inhibition by direct depolarization or hyperpolarization of the membrane of MSNs, and their effects are largely restricted to neuromodulatory actions on voltage-gated sodium, potassium and calcium channels 49.•, 50., 51.. By contrast, dopamine

Conclusions

The neostriatum, similar to the hippocampus and neocortex, possesses a variety of GABAergic interneurons defined on the basis of their chemical and physiological phenotypes (Figure 4). Each of these is in a position to influence both the timing and the pattern of firing of the principal neuron in the neostriatum. Their precise roles remain to be elucidated but will depend upon their afferent input, the localization of their terminals on MSNs and when they fire in relation to MSN activity.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by NS34865 and a Human Frontier Science Program Short-Term Fellowshop (JM Tepper) and the Medical Research Council, UK (JP Bolam). We are grateful to PJ Magill for stimulating discussions and suggestions for the organization of the review. We thank CR Lee for the physiological traces of the cholinergic neuron in Figure 1, P Jays for the reconstruction of the FS interneuron in Figure 1 and CJ Wilson for the aspiny neuron reconstruction in Figure 1. We thank B Micklem and

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