Alterations of neuronal activity due to changes in GABAA receptors (GABAAR) mediating tonic inhibition influence different hippocampal functions. Gabra5-null mice and α5 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 α5-GABAAR 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 α5-GABAARs to granule cell development, using retroviral vectors expressing eGFP for labeling precursor cells in the subgranular zone. Global α5-GABAAR knockout (α5-KO) mice showed no alterations in migration and morphological development of eGFP-positive granule cells. However, upregulation of α1 subunit-immunoreactivity was observed in the hippocampal formation and cerebral cortex. In contrast, partial gene inactivation in α5-heterozygous (α5-het) mice, as well as single-cell deletion of Gabra5 in newborn granule cells from α5-floxed mice, caused severe alterations of migration and dendrite development. In α5-het mice, retrovirally mediated overexpression of Cdk5 resulted in normal migration and dendritic branching, suggesting that Cdk5 cooperates with α5-GABAARs to regulate neuronal development. These results show that minor imbalance of α5-GABAAR-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.
Bibliographical noteFunding Information:
JMF was supported by the Swiss National Science Foundation (Grant 310030_146120). UR was supported by award number R01GM086448 from the National Institute of General Medical Sciences of the National Institute of Health and award numbers R01MH080006 and R01MH095905 of the National Institute of Mental Health. We are grateful to Dr. Sebastian Jessberger (University of Zurich) for generously providing the Cdk5 construct and the Cre-mCherry retroviral vector, Claire de Groot and Yuen-Chen Tsai for help with virus production and qPCR analysis, and to Dr. Elif Engin for critical comments on the manuscript. Abbreviations ACSF artificial cerebrospinal fluid AUC area under the curve GCL granule cell layer SGZ subgranular zone
© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd
- adult neurogenesis
- targeted gene deletion