An NMDA Receptor-Dependent Mechanism Underlies Inhibitory Synapse Development

• GABAergic synapse development requires glutamate receptors
• Ca2+ influx through NMDARs is important for GABAergic synapse development
• The NMDAR GluN1 C0 domain is critical for inhibitory synapse development
• Ca2+/CaM binding to the GluN1 C0 domain controls inhibitory synapse development

SummaryIn the mammalian brain, GABAergic synaptic transmission provides inhibitory balance to glutamatergic excitatory drive and controls neuronal output. The molecular mechanisms underlying the development of GABAergic synapses remain largely unclear. Here, we report that NMDA-type ionotropic glutamate receptors (NMDARs) in individual immature neurons are the upstream signaling molecules essential for GABAergic synapse development, which requires signaling via Calmodulin binding motif in the C0 domain of the NMDAR GluN1 subunit. Interestingly, in neurons lacking NMDARs, whereas GABAergic synaptic transmission is strongly reduced, the tonic inhibition mediated by extrasynaptic GABAA receptors is increased, suggesting a compensatory mechanism for the lack of synaptic inhibition. These results demonstrate a crucial role for NMDARs in specifying the development of inhibitory synapses, and suggest an important mechanism for controlling the establishment of the balance between synaptic excitation and inhibition in the developing brain.

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