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

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.