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

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 GABAA receptors (α5-GABAARs) 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-GABAARs. Computational modeling shows that the voltage-dependent amplification of α5-GABAAR opening in young neurons is crucial for inhibition of AP firing to generate balanced and sparse firing activity, even with depolarized GABA reversal potential. [Display omitted] •Adult-born young GCs express α5-GABARs in SOM- and PV-interneuron synapses•Mature GCs express α5-GABARs only in dendritic SOM-interneuron synapses•α5-GABARs show nonlinear gating with large conductance at AP threshold•α5-GABARs support effective shunting inhibition of AP firing with depolarized EGABA α5-Subunit-containing GABAA receptors are believed to be mainly localized outside synapses. Lodge et al. show that these receptors are expressed in GABAergic synapses onto young hippocampal neurons, generating powerful inhibition. During maturation, these receptors are excluded from perisomatic synapses, while they continue to be present in dendrite-targeting synapses.