Spatiotemporal specificity of GABAA receptor-mediated regulation of adult hippocampal neurogenesis

GABAergic transmission regulates adult neurogenesis by exerting negative feedback on cell proliferation and enabling dendrite formation and outgrowth. Further, GABAergic synapses target differentiating dentate gyrus granule cells prior to formation of glutamatergic connections. GABA(A) receptors (GABA(A)Rs) mediating tonic (extrasynaptic) and phasic (synaptic) transmission are molecularly and functionally distinct, but their specific role in regulating adult neurogenesis is unknown. Using global and single-cell targeted gene deletion of subunits contributing to the assembly of GABA(A)Rs mediating tonic (alpha 4, delta) or phasic (alpha 2) GABAergic transmission, we demonstrate here in the dentate gyrus of adult mice that GABA(A)Rs containing alpha 4, but not delta, subunits mediate GABAergic effects on cell proliferation, initial migration and early dendritic development. In contrast, alpha 2-GABA(A)Rs cell-autonomously signal to control positioning of newborn neurons and regulate late maturation of their dendritic tree. In particular, we observed pruning of distal dendrites in immature granule cells lacking the alpha 2 subunit. This alteration could be prevented by pharmacological inhibition of thrombospondin signaling with chronic gabapentin treatment, shown previously to reduce glutamatergic synaptogenesis. These observations point to homeostatic regulation of inhibitory and excitatory inputs onto newborn granule cells under the control of alpha 2-GABA(A)Rs. Taken together, the availability of distinct GABA(A)R subtypes provides a molecular mechanism endowing spatiotemporal specificity to GABAergic control of neuronal maturation in adult brain.