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Partial inactivation of GABA$_A$ receptors containing the α5 subunit affects the development of adult-born dentate gyrus granule cells


Deprez, Francine; Vogt, Fabia; Floriou-Servou, Amalia; Lafourcade, Carlos; Rudolph, Uwe; Tyagarajan, Shiva K; Fritschy, Jean-Marc (2016). Partial inactivation of GABA$_A$ receptors containing the α5 subunit affects the development of adult-born dentate gyrus granule cells. European Journal of Neuroscience, 44(5):2258-2271.

Abstract

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 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-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 α5-GABA$_A$Rs to granule cell development, using retroviral vectors expressing eGFP for labeling precursor cells in the subgranular zone. Global α5-GABA$_A$R 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-GABA$_A$Rs to regulate neuronal development. These results show that minor imbalance of α5-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.

Abstract

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 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-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 α5-GABA$_A$Rs to granule cell development, using retroviral vectors expressing eGFP for labeling precursor cells in the subgranular zone. Global α5-GABA$_A$R 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-GABA$_A$Rs to regulate neuronal development. These results show that minor imbalance of α5-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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:September 2016
Deposited On:17 Jan 2017 13:31
Last Modified:17 Jan 2017 13:31
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0953-816X
Publisher DOI:https://doi.org/10.1111/ejn.13329
PubMed ID:27364953

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