Partial inactivation of GABAA receptors containing the 5 subunit affects the development of adult-born dentate gyrus granule cells

Alterations of neuronal activity due to changes in GABA(A) receptors (GABA(A)R) mediating tonic inhibition influence different hippocampal functions. Gabra5-null mice and 5 subunit((H105R)) knock-in mice exhibit signs of hippocampal dysfunction, but are capable of improved performance in several learning and memory tasks. Accordingly, alleviating abnormal GABAergic tonic inhibition in the hippocampal formation by selective 5-GABA(A)R modulators represents a possible therapeutic approach for several intellectual deficit disorders. Adult neurogenesis in the dentate gyrus is an important facet of hippocampal plasticity; it is regulated by tonic GABAergic transmission, as shown by deficits in proliferation, migration and dendritic development of adult-born neurons in Gabra4-null mice. Here, we investigated the contribution of 5-GABA(A)Rs to granule cell development, using retroviral vectors expressing eGFP for labeling precursor cells in the subgranular zone. Global 5-GABA(A)R knockout (5-KO) mice showed no alterations in migration and morphological development of eGFP-positive granule cells. However, upregulation of 1 subunit-immunoreactivity was observed in the hippocampal formation and cerebral cortex. In contrast, partial gene inactivation in 5-heterozygous (5-het) mice, as well as single-cell deletion of Gabra5 in newborn granule cells from 5-floxed mice, caused severe alterations of migration and dendrite development. In 5-het mice, retrovirally mediated overexpression of Cdk5 resulted in normal migration and dendritic branching, suggesting that Cdk5 cooperates with 5-GABA(A)Rs to regulate neuronal development. These results show that minor imbalance of 5-GABA(A)R-mediated transmission may have major consequences for neuronal plasticity; and call for caution upon chronic therapeutic use of negative allosteric modulators acting at these receptors.