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

Francine Deprez, Fabia Vogt, Amalia Floriou-Servou, Carlos Lafourcade, Uwe Rudolph, Shiva K. Tyagarajan, Jean Marc Fritschy

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

11 Citas (Scopus)

Resumen

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.
Idioma originalInglés estadounidense
Páginas (desde-hasta)2258-2271
Número de páginas14
PublicaciónEuropean Journal of Neuroscience
Volumen44
N.º5
DOI
EstadoPublicada - 1 sep 2016
Publicado de forma externa

Palabras clave

  • adult neurogenesis
  • Cdk5
  • dendrites
  • migration
  • retrovirus
  • targeted gene deletion

Huella Profundice en los temas de investigación de 'Partial inactivation of GABA<sub>A</sub> receptors containing the α5 subunit affects the development of adult-born dentate gyrus granule cells'. En conjunto forman una huella única.

Citar esto