Sparsification of AP firing in adult-born hippocampal granule cells via voltage-dependent α5-GABAA receptors

Abstract

GABA can depolarize immature neurons close to the action potential (AP) threshold in development and adult neurogenesis. Nevertheless, GABAergic synapses effectively inhibit AP firing in newborn granule cells of the adult hippocampus as early as two weeks post-mitosis. The underlying mechanisms are largely unclear. Here, we analyze GABAergic inputs in newborn hippocampal granule cells mediated by soma-targeting parvalbumin and dendrite-targeting somatostatin interneurons. Surprisingly, both interneuron subtypes activate α5-subunit-containing GABA_A receptors (α5-GABA_ARs) in young neurons, showing a nonlinear voltage dependence with increasing conductance around the AP threshold. By contrast, in mature cells, parvalbumin interneurons mediate linear GABAergic synaptic currents lacking α5-subunits, while somatostatin interneurons continue to target nonlinear α5-GABA_ARs. Computational modeling shows that the voltage-dependent amplification of α5-GABA_AR opening in young neurons is crucial for inhibition of AP firing to generate balanced and sparse firing activity, even with depolarized GABA reversal potential.

Keywords: GABA receptors; GABAergic excitation; NMDA receptors; adult neurogenesis; brain development; excitation-inhibition balance; granule cells; hippocampus; shunting inhibition; α5-GABA(A) receptors.