Target Selectivity of Feedforward Inhibition by Striatal Fast-Spiking Interneurons

Abstract

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.

Local and afferent synaptic pathways in the striatal microcircuitry

“…However, this inhibitory blanket does not equally influence all types of neighboring neurons but rather displays selectivity in its targeting. In the striatum, PV interneurons selectively avoid cholinergic interneurons, while robustly inhibiting neighboring MSNs [28 ], thus exhibiting a high degree of selectivity in the local circuitry, similar to the local target preference found in neocortical interneurons [29] (Figure 1). …”

“…(a) Schematic representation of an experiment showing robust inhibition of MSNs by optogenetic activation of fast-spiking PV-expressing interneurons and avoidance of a simultaneously recorded neighboring cholinergic interneuron (CHIN). (b) Blanket of feed-forward inhibition by PV interneurons onto MSNs, with 'holes' representing the avoided cholinergic interneurons.Adapted from[27,28 ].…”

Chronic Stress Alters Striosome-Circuit Dynamics, Leading to Aberrant Decision-Making

“…We injected 5 PV-Cre transgenic mice with excitatory opsin (AAV5-EF1a-DIO-C1V1(E122T/E162T)-TS-EYFP) and 4 with inhibitory opsin (AAV5-EF1a-DIO-eArch3.0-EYFP) viruses. Over 90% of the optogenetically identified neurons (92%, 39 out of 42) exhibited narrow waveforms and a wide spectrum of firing rates, indicating that indeed striatal FSIs overlap strongly with PV + neurons (Kawaguchi, 1993; Kim et al, 2016; Szydlowski et al, 2013) (Figures 3H, S4M and S4N). …”

“…Second, because of the known overlap of parvalbumin-immunoreactive (PV + ) cells and FSIs (Kawaguchi, 1993; Szydlowski et al, 2013), we used histology to analyze the number of PV + cells in control mice and chronically stressed mice immediately (n = 10 per group) or one month (n = 14 per group) after immobilization stress. The PV + cell count decreased only slightly and insignificantly at both time points (Figure 3G), suggesting that the primary stress effect was not neuronal death, but a reduction in FSI firing rates.…”

Striatal Local Circuitry: A New Framework for Lateral Inhibition

“…Interestingly, despite this evidence of nicotinic stimulation and depolarizing responses to cholinergic stimulation, FSIs do not appear to play a major role in the disynaptic inhibition of SPNs through cholinergic interneurons (Nelson et al, 2014b). CIN to FSI synaptic connections are not reciprocal as it has been shown that FSI cells do not form synapses onto cholinergic interneurons (Straub et al, 2016; Szydlowski et al, 2013). …”