Paracrine Role for Somatostatin Interneurons in the Assembly of Perisomatic Inhibitory Synapses

GABAergic interneurons represent a heterogenous group of cell types in neocortex that can be clustered based on developmental origin, morphology, physiology, and connectivity. Two abundant populations of cortical GABAergic interneurons include the low-threshold, somatostatin (SST)-expressing cells and the fast-spiking, parvalbumin (PV)-expressing cells. While SST⁺ and PV⁺ interneurons are both early born and migrate into the developing neocortex at similar times, SST⁺ cells are incorporated into functional circuits prior to PV⁺ cells. During this early period of neural development, SST⁺ cells play critical roles in the assembly and maturation of other cortical circuits; however, the mechanisms underlying this process remain poorly understood. Here, using both sexes of conditional mutant mice, we discovered that SST⁺ interneuron-derived Collagen XIX, a synaptogenic extracellular matrix protein, is required for the formation of GABAergic, perisomatic synapses by PV⁺ cells. These results, therefore, identify a paracrine mechanism by which early-born SST⁺ cells orchestrate inhibitory circuit formation in the developing neocortex.SIGNIFICANCE STATEMENT Inhibitory interneurons in the cerebral cortex represent a heterogenous group of cells that generate the inhibitory neurotransmitter GABA. One such interneuron type is the low-threshold, somatostatin (SST)-expressing cell, which is one of the first types of interneurons to migrate into the cerebral cortex and become incorporated into functional circuits. In addition, to contributing important roles in controlling the flow of information in the adult cerebral cortex, SST⁺ cells play important roles in the development of other neural circuits in the developing brain. Here, we identified an extracellular matrix protein that is released by these early-born SST⁺ neurons to orchestrate inhibitory circuit formation in the developing cerebral cortex.