| First Author | Deprez F | Year | 2016 |
| Journal | Eur J Neurosci | Volume | 44 |
| Issue | 5 | Pages | 2258-71 |
| PubMed ID | 27364953 | Mgi Jnum | J:234234 |
| Mgi Id | MGI:5789546 | Doi | 10.1111/ejn.13329 |
| Citation | Deprez F, et al. (2016) Partial inactivation of GABAA receptors containing the alpha5 subunit affects the development of adult-born dentate gyrus granule cells. Eur J Neurosci 44(5):2258-71 |
| abstractText | Alterations of neuronal activity due to changes in GABAA receptors (GABAA R) mediating tonic inhibition influence different hippocampal functions. Gabra5-null mice and alpha5 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 alpha5-GABAA 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 alpha5-GABAA Rs to granule cell development, using retroviral vectors expressing eGFP for labeling precursor cells in the subgranular zone. Global alpha5-GABAA R knockout (alpha5-KO) mice showed no alterations in migration and morphological development of eGFP-positive granule cells. However, upregulation of alpha1 subunit-immunoreactivity was observed in the hippocampal formation and cerebral cortex. In contrast, partial gene inactivation in alpha5-heterozygous (alpha5-het) mice, as well as single-cell deletion of Gabra5 in newborn granule cells from alpha5-floxed mice, caused severe alterations of migration and dendrite development. In alpha5-het mice, retrovirally mediated overexpression of Cdk5 resulted in normal migration and dendritic branching, suggesting that Cdk5 cooperates with alpha5-GABAA Rs to regulate neuronal development. These results show that minor imbalance of alpha5-GABAA 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. |
