Kash, S. F.Tecott, L. H.Hodge, C.Baekkeskov, S.2015-12-022015-12-02199910.1073/pnas.96.4.1698https://infoscience.epfl.ch/handle/20.500.14299/120901The larger isoform of the enzyme glutamate decarboxylase, GAD67, synthesizes >90% of basal levels of γ-aminobutyric acid (GABA) in the brain. In contrast, the smaller isoform, GAD65, has been implicated in the fine-tuning of inhibitory neurotransmission. Mice deficient in GAD65 exhibit increased anxiety-like responses in both the open field and elevated zero maze assays. Additionally, GAD65-deficient mice have a diminished response to the anxiolytics diazepam and pentobarbital, both of which interact with GABA-A receptors in a GABA-dependent fashion to facilitate GABAergic neurotransmission. Loss of GAD65-generated GABA does not appear to result in compensatory postsynaptic GABA-A receptor changes based on radioligand receptor binding studies, which revealed no change in the postsynaptic GABA-A receptor density. Furthermore, mutant and wild-type animals do not differ in their behavioral response to muscimol, which acts independently of the presence of GABA. We propose that stress-induced GABA release is impaired in GAD65-deficient mice, resulting in increased anxiety-like responses and a diminished response to the acute effects of drugs that facilitate the actions of released GABA.text::journal::journal article::research article