Distinct Roles of GABAergic Interneurons in the Regulation of Striatal Output Pathways

Abstract

Striatal GABAergic microcircuits are critical for motor function, yet their properties remain enigmatic due to difficulties in targeting striatal interneurons for electrophysiological analysis. Here, we use Lhx6-GFP transgenic mice to identify GABAergic interneurons and investigate their regulation of striatal direct-and indirect-pathway medium spiny neurons (MSNs). We find that the two major interneuron populations, persistent low-threshold spiking (PLTS) and fast spiking (FS) interneurons, differ substantially in their excitatory inputs and inhibitory outputs. Excitatory synaptic currents recorded from PLTS interneurons are characterized by a small, nonrectifying AMPA receptor-mediated component and a NMDA receptor-mediated component. In contrast, glutamatergic synaptic currents in FS interneurons have a large, strongly rectifying AMPA receptor-mediated component, but no detectable NMDA receptor-mediated responses. Consistent with their axonal morphology, the output of individual PLTS interneurons is relatively weak and sparse, whereas FS interneurons are robustly connected to MSNs and other FS interneurons and appear to mediate the bulk of feedforward inhibition. Synaptic depression of FS outputs is relatively insensitive to firing frequency, and dynamic-clamp experiments reveal that these shortterm dynamics enable feedforward inhibition to remain efficacious across a broad frequency range. Surprisingly, we find that FS interneurons preferentially target direct-pathway MSNs over indirect-pathway MSNs, suggesting a potential mechanism for rapid pathway-specific regulation of striatal output pathways.

Substantia nigra dopaminergic neurons and striatal interneurons are engaged in three parallel but interdependent postnatal neurotrophic circuits

“…We recorded GABAergic miniature inhibitory postsynaptic currents (mIPSCs) from striatal MSN, which receive a strong perisomatic inhibition from FS interneurons (Gittis et al, 2010). The amplitude, kinetic characteristics, and frequency of these mIPSCs were unaltered in 4‐ and 10‐month‐old PV‐Smo mice (Figure 3a,b), indicating that Smo deletion in FS does not have a strong effect over striatal function.…”

GDNF Is Predominantly Expressed in the PV+ Neostriatal Interneuronal Ensemble in Normal Mouse and after Injury of the Nigrostriatal Pathway

“…PVϩ cells constitute a unique network interconnected by electrical synapses due to dendrodendritic gap junctions, which enable them to fire almost synchronously. Striatal fast-spiking PV cells can resonate at the gamma frequency (Sharott et al, 2009) and are considered to be the major component of a powerful feedforward inhibition that controls spike timing in MSNs, thereby regulating striatal output (Gittis et al, 2010;Tepper et al, 2010;Chuhma et al, 2011). GDNF production in PVϩ neurons could be advantageous if the trophic factor is released during periods of activity of the cell functional ensemble (Lonka-Nevalaita et al, 2010), thus interacting with axon terminals of practically the entire nigrostriatal pathway.…”

Nitric Oxide Modulation of the Basal Ganglia Circuitry: Therapeutic Implication for Parkinson's Disease and Other Motor Disorders

“…Conversely, interneurons exhibit a short lasting decrease in response to conditioned stimuli [89]. A more detailed classification identifies amongst interneurons [90] parvalbumin-positive GABAergic fast-spiking ones (about < 1%), because of their brief spike duration [91,92] Nitrergic interneurons exert slower neuromodulatory effects on their postsynaptic targets rather than fast synaptic effects [93]. The lack of synaptic responses in MSNs might be due to a preferential release of NO rather than to GABA.…”