ReviewFeedforward and feedback inhibition in neostriatal GABAergic spiny neurons
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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