Regulation of synapse development by Vgat deletion from ErbB4-positive interneurons

Abstract

GABA signaling has been implicated in neural development; however, in vivo genetic evidence is missing because mutant mice lacking GABA activity die prematurely. Here, we studied synapse development by ablating vesicular GABA transporter (Vgat) in ErbB4 + interneurons. We show that inhibitory axo-somatic synapses onto pyramidal neurons vary from one cortical layer to another; however, inhibitory synapses on axon initial segments (AISs) were similar across layers. Conversely, parvalbumin-positive (PV + )/ErbB4 + interneurons and PV-only interneurons receive a higher number of inhibitorysynapses from PV + ErbB4 + interneurons compared with ErbB4-only interneurons. Vgat deletion from ErbB4 + interneurons reduced axo-somatic or axo-axonic synapses from PV + ErbB4 + interneurons onto excitatory neurons. This effect was associated with corresponding changes in neurotransmission. However, the Vgat mutation seemed to have little effect on inhibitory synapses onto PV + and/or ErbB4 + interneurons. Interestingly, perineuronal nets, extracellular matrix structures implicated in maturation, survival, protection, and plasticity of PV + interneurons, were increased in the cortex of ErbB4-Vgat -/- mice. No apparent difference was observed between males and females. These results demonstrate that Vgat of ErbB4 + interneurons is essential for the development of inhibitory synapses onto excitatory neurons and suggest a role of GABA in circuit assembly.