REGULATION OF SYNAPSE DEVELOPMENT BY GABA ACTIVITY OF ERBB4-POSITIVE INTERNEURONS

Abstract

GABA activity has been implicated in neural development; however, in vivo genetic evidence is missing because mutant mice lacking GABA activity die prematurely. Here, we studied postnatal synapse development in ErbB4-Vgat-/- mice where Vgat was deleted in ErbB4+ interneurons. We show that the number of inhibitory axo-somatic synapses onto pyramidal neurons is layer-specific; however, inhibitory synapses on axon initial segments (AISs) were similar from layer to layer. On the other hand, PV+ErbB4+ interneurons and PV-only interneurons receive higher number of inhibitory synapses from PV+ErbB4+ interneurons, compared with ErbB4-only interneurons. Erbb4-Vgat-/- mice exhibited fewer inhibitory synapses from PV+ErbB4+ interneurons onto excitatory neurons (either axo-somatic or axo-axonic), compared with control mice. The Vgat mutation seemed to have little effect on inhibitory synapses onto PV+ and/or ErbB4+ interneurons. These morphological alterations were associated with concomitant changes in neurotransmission. Finally, perineuronal nets were increased in the cortex of ErbB4-Vgat-/- mice. These results demonstrate that GABA activity from ErbB4+ interneurons specifically regulates the development of inhibitory synapses onto excitatory neurons and provides in vivo evidence for a critical role of GABA activity in circuit assembly.