Elsevier

Brain Research Reviews

Volume 58, Issue 2, August 2008, Pages 272-281
Brain Research Reviews

Review
Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons

https://doi.org/10.1016/j.brainresrev.2007.10.008Get rights and content

Abstract

There are two distinct inhibitory GABAergic circuits in the neostriatum. The feedforward circuit consists of a relatively small population of GABAergic interneurons that receives excitatory input from the neocortex and exerts monosynaptic inhibition onto striatal spiny projection neurons. The feedback circuit comprises the numerous spiny projection neurons and their interconnections via local axon collaterals. This network has long been assumed to provide the majority of striatal GABAergic inhibition and to sharpen and shape striatal output through lateral inhibition, producing increased activity in the most strongly excited spiny cells at the expense of their less strongly excited neighbors. Recent results, mostly from recording experiments of synaptically connected pairs of neurons, have revealed that the two GABAergic circuits differ markedly in terms of the total number of synapses made by each, the strength of the postsynaptic response detected at the soma, the extent of presynaptic convergence and divergence and the net effect of the activation of each circuit on the postsynaptic activity of the spiny neuron. These data have revealed that the feedforward inhibition is powerful and widespread, with spiking in a single interneuron being capable of significantly delaying or even blocking the generation of spikes in a large number of postsynaptic spiny neurons. In contrast, the postsynaptic effects of spiking in a single presynaptic spiny neuron on postsynaptic spiny neurons are weak when measured at the soma, and unable to significantly affect spike timing or generation. Further, reciprocity of synaptic connections between spiny neurons is only rarely observed. These results suggest that the bulk of the fast inhibition that has the strongest effects on spiny neuron spike timing comes from the feedforward interneuronal system whereas the axon collateral feedback system acts principally at the dendrites to control local excitability as well as the overall level of activity of the spiny neuron.

Introduction

The basal ganglia comprise the largest subcortical system in the brain extending from the telencephalon through the midbrain. Among the many unique features of the basal ganglia is the fact that it is composed almost entirely (> 98.8%; see Tepper et al., 2007) of GABAergic neurons. The neostriatum, the largest single nucleus in the basal ganglia, not surprisingly comprises almost entirely GABAergic neurons. The vast majority of these, at least 95%, in species ranging from rodent to primate (Kemp and Powell, 1971, Luk and Sadikot, 2001, Wilson, 2004 but see also Graveland and DiFiglia, 1985) are medium-sized spiny projection neurons that are also the only source of output from the nucleus. The remaining cell types comprise large aspiny cholinergic interneurons, and at least 3 distinct types of GABAergic interneurons (Kawaguchi, 1993, Kawaguchi et al., 1995).

These GABAergic interneurons were first characterized electrophysiologically, morphologically and neurochemically by Kawaguchi and colleagues (Kawaguchi, 1993, Kubota et al., 1993, Kubota and Kawaguchi, 1994, Kawaguchi et al., 1995). These investigators described a medium-sized GABAergic aspiny neuron with a fast-spiking (FS) phenotype that was immunoreactive for the calcium binding protein, parvalbumin (PV). The second aspiny interneuron, subsequently shown to be GABAergic (Kubota and Kawaguchi, 1994) was described that it fired low threshold spikes and exhibited a persistent depolarizing plateau potential in response to depolarizing current injection that long outlasted the depolarizing stimuli which was termed the PLTS neuron (Kawaguchi et al., 1995), and in later papers just the LTS neuron (e.g., Kubota and Kawaguchi, 2000). The PLTS electrophysiological phenotype was shown to belong to a striatal interneuron previously shown to selectively express the neuropeptides somatostatin and NPY, and nitric oxide synthase (Emson et al., 1993). The third medium-sized aspiny GABAergic neuron was identified as immunoreactive for calretinin but not for any of the other calcium binding proteins or neuropeptides found in other striatal interneurons (Kawaguchi et al., 1995). Its electrophysiological phenotype was not described at the time and still remains unknown.

Although most of the neurons in the striatum are GABAergic, most of the synapses are not, some 80% consisting of asymmetric glutamatergic synapses originating from the cortex and thalamus (Kemp and Powell, 1971, Ingham et al., 1998; for recent review, see Wilson, 2007). Nevertheless, GABAergic inhibition plays the most important role in the modulation of striatal output. One of the clearest demonstrations of this is the fact that blockade of striatal GABAA receptors by local application of bicuculline in vivo increases the spontaneous firing rate of striatal neurons by a factor of 3 or more (Nisenbaum and Berger, 1992).

There are two major potential sources of the fast GABAergic inhibition in striatum: feedforward inhibition from the GABAergic interneurons and feedback inhibition from the axon collaterals of the spiny neurons themselves. As the number of GABAergic synapses formed onto spiny neurons by the spiny cell axon collaterals is significantly greater than the number formed by the interneurons (e.g., Guzman et al., 2003, Koós et al., 2004), all other things being equal, one would expect the axon collateral inhibitory feedback system to be the predominant player in the control of spiny cell activity and spike timing, as proposed by many others in the past. Striatal organization was most often conceived of as a lateral inhibitory network (Groves, 1983, Wickens et al., 1991, Wickens et al., 1995, Beiser and Houk, 1998, Bar-Gad and Bergman, 2001). Lateral inhibitory networks are typically considered to consist of each output neuron making symmetric reciprocal inhibitory synapses onto its neighbors. However, more recent data obtained from recording from synaptically connected interneuron–spiny cell and spiny cell–spiny cell pairs over the past 5 years are inconsistent with such a model of striatal function and suggest a significantly different type of functional organization.

Section snippets

Fast-spiking interneurons

By far the best-characterized GABAergic interneurons are those that express parvalbumin (PV). 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 smaller soma and a relatively restricted and varicose dendritic arborization in the region of 200–300 μm in diameter, and the other displaying a larger cell body and a more extended non-varicose dendritic field 500–600 μm in diameter (Kita

Spiny cell axon collaterals and feedback inhibition

In addition to their extrastriatal projections, the spiny projection neurons give rise to a relatively dense local axon collateral arborization that is approximately coextensive with and usually extends beyond (sometimes far beyond) the dendritic arborization of the parent cell (Wilson and Groves, 1980, Kawaguchi et al., 1990). Electron microscopic analysis of intracellularly or immunocytochemically labeled spiny cell axons revealed that the principal targets of these local GABAergic

Summary

In conclusion, there are two main types of GABAergic circuitry in the striatum, a feedforward inhibitory circuit mediated by several different types of GABAergic interneurons synapsing on spiny cells and an inhibitory feedback circuit mediated by the axon collaterals of the spiny neurons synapsing on other spiny neurons. There are far more inhibitory synapses in the feedback circuit than in the feedforward circuit, but each of the synapses is far less effective at controlling spiking in the

Acknowledgments

This work was supported by NS034865 (to JMT), NS052370 (to TK) and NS37760 (to CJW).

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