Regulation of Synapse Development by<i>Vgat</i>Deletion from ErbB4-Positive Interneurons

Abstract

GABA signaling has been implicated in neural development; however, <i>in vivo</i> genetic evidence is missing because mutant mice lacking GABA activity die prematurely. Here, we studied synapse development by ablating vesicular GABA transporter (<i>Vgat</i>) 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 inhibitory synapses from PV⁺ErbB4⁺ interneurons compared with ErbB4-only interneurons. <i>Vgat</i> 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 <i>Vgat</i> 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 <i>Vgat</i> of ErbB4⁺ interneurons is essential for the development of inhibitory synapses onto excitatory neurons and suggest a role of GABA in circuit assembly.<b>SIGNIFICANCE STATEMENT</b> GABA has been implicated in neural development, but <i>in vivo</i> genetic evidence is missing because mutant mice lacking GABA die prematurely. Here, we ablated <i>Vgat</i> in ErbB4⁺ interneurons in an inducible manner. We provide evidence that the formation of inhibitory and excitatory synapses onto excitatory neurons requires <i>Vgat</i> in interneurons. In particular, inhibitory axo-somatic and axo-axonic synapses are more vulnerable. Our results suggest a role of GABA in circuit assembly.