Ablation of Gabra5 Influences Corticosterone Levels and Anxiety-like Behavior in Mice

Genes (Basel). 2023 Jan 21;14(2):285. doi: 10.3390/genes14020285.

Abstract

Stress responses are activated by the hypothalamic-pituitary-adrenal axis (HPA axis), culminating in the release of glucocorticoids. During prolonged periods of secretion of glucocorticoids or inappropriate behavioral responses to a stressor, pathologic conditions may occur. Increased glucocorticoid concentration is linked to generalized anxiety, and there are knowledge gaps regarding its regulation. It is known that the HPA axis is under GABAergic control, but the contribution of the individual subunits of the GABA receptor is largely unknown. In this study, we investigated the relationship between the α5 subunit and corticosterone levels in a new mouse model deficient for Gabra5, which is known to be linked to anxiety disorders in humans and phenologs observed in mice. We observed decreased rearing behavior, suggesting lower anxiety in the Gabra5-/- animals; however, such a phenotype was absent in the open field and elevated plus maze tests. In addition to decreased rearing behavior, we also found decreased levels of fecal corticosterone metabolites in Gabra5-/- mice indicating a lowered stress response. Moreover, based on the electrophysiological recordings where we observed a hyperpolarized state of hippocampal neurons, we hypothesize that the constitutive ablation of the Gabra5 gene leads to functional compensation with other channels or GABA receptor subunits in this model.

Keywords: GABA receptor; anxiety; behavior; corticosterone; mouse model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety
  • Corticosterone*
  • Glucocorticoids*
  • Humans
  • Hypothalamo-Hypophyseal System / metabolism
  • Mice
  • Pituitary-Adrenal System / metabolism
  • Receptors, GABA / metabolism
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism

Substances

  • Corticosterone
  • Glucocorticoids
  • Receptors, GABA
  • GABRA5 protein, human
  • Receptors, GABA-A
  • Gabra5 protein, mouse

Grants and funding

This research was supported by the Czech Academy of Sciences RVO 68378050, LM2018126 Czech Centre for Phenogenomics provided by MEYS CR, OP RDE CZ.02.1.01/0.0/0.0/16_013/0001789 (Upgrade of the Czech Centre for Phenogenomics: developing towards translation research by MEYS and ESIF), OP RDE CZ.02.1.01/0.0/0.0/18_046/0015861 (CCP Infrastructure Upgrade II by MEYS and ESIF), and OP RDI CZ.1.05/2.1.00/19.0395 (Higher quality and capacity for transgenic models by MEYS and ERDF), and funding was received from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska–Curie grant agreement “Improving Genome Editing Efficiency (IMGENE)”, grant agreement no 765269. In addition, this study received funding from the NGO “Association of Gene Therapy (ASGENT)”, Czechia (https://asgent.org/, accessed on 1 March 2022). The project was also supported by the Strategy AV21 Research programme “Towards Precision Medicine and Gene Therapy”. Additionally, the work was supported by GACR 19-09283S.