VIP subtype-specific role for Prox1 in circuit integration

VIP interneurons are essential players in the modulation and development of cortical circuits. They can be roughly subdivided into two types; the VIP bipolar and multipolar cells. Here we explore the role of the transcription factor Prox1 as a regulator of cell autonomous genetic programs that guide the integration of VIP cells into their circuits in early post-natal life. We find that the synaptic integration of VIP bipolar and multipolar cells is affected differently by a Prox1 knock-out. While in VIP bipolar cells knocking-out Prox1 reduces the number of spontaneous EPSCs, it increases the frequency of sEPSCs in VIP multipolar cells. Furthermore, synaptic release probability onto multipolar cells increases when Prox1 is removed while in bipolar cells it is unaffected. An RNA sequencing screen revealed the trans-synaptic protein Elfn1 as a downstream target of Prox1. Further electrophysiological recordings showed that Elfn1 is specifically regulating release probability onto multipolar VIP cells. Finally, pharmacological blocking of the Elfn1 binding partner mGluR7 proved that knocking out Prox1 specifically reduces Elfn1 function in VIP multipolar but not in bipolar cells.