Nova proteins direct synaptic integration of somatostatin interneurons through activity- dependent alternative splicing

Somatostatin interneurons are the earliest born population of inhibitory cells. They are crucial to support normal brain development and function; however, the mechanisms underlying their integration into nascent cortical circuitry are not well understood. In this study, we begin by demonstrating that the maturation of somatostatin interneurons is activity dependent. We then investigated the relationship between activity, alternative splicing and synapse formation within this population. Specifically, we discovered that the Nova family of RNA-binding proteins are activity-dependent and are essential for the maturation of somatostatin interneurons, as well as their afferent and efferent connectivity. Moreover, in somatostatin interneurons, Nova2 preferentially mediates the alternative splicing of genes required for axonal formation and synaptic function. Hence, our work demonstrates that the Nova family of proteins are centrally involved in coupling developmental neuronal activity to cortical circuit formation. Overall design: Somatostatin SST interneurons were isolated by FACS from the S1 cortex and subjected to RNAseq library preparation following standard Illumnia guidelines.