Post-mitotic Prox1 expression controls the final specification of cortical VIP interneuron subtypes

Summary Neuronal identity is controlled in multiple developmental steps by key transcription factors that determine the unique properties of a cell. During embryogenesis, the transcription factor Prox1 has been shown to regulate VIP interneuron migration, survival, and as a result, circuit integration. Here, we explore the role of Prox1 as a regulator of genetic programs that guide the final specification of VIP interneuron subtypes in early post-natal life. Using in-vitro electrophysiology we find that post-natal removal of Prox1 differentially affects the synaptic integration of VIP bipolar and multipolar subtypes. RNA sequencing reveals that one of the downstream targets of Prox1 is the postsynaptic protein Elfn1, a constitutive regulator of presynaptic release probability. Genetic, pharmacological and electrophysiological experiments demonstrate that knocking out Prox1 reduces Elfn1 function in VIP multipolar but not in bipolar cells. Thus, in addition to the activity-dependent and contextual processes that finalize developmental trajectories, genetic programs engaged by Prox1 control the differentiation and connectivity of VIP interneuron subtypes.