Target selectivity of feedforward inhibition by striatal fast-spiking interneurons

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.