Increased anxiety and altered responses to anxiolytics in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase.

Article date: 1999/2/17

PubMed ID: 1321158

Journal name: Proceedings of the National Academy of Sciences of the United States of America (ISSN: 0027-8424)


The larger isoform of the enzyme glutamate decarboxylase, GAD67, synthesizes >90% of basal levels of gamma-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.

Author List: Kash S F, Tecott L H, Hodge C, Baekkeskov S

Publication Types: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.

Substances mentioned in the article: Anti-Anxiety Agents; Isoenzymes; Receptors, GABA-A; gamma-Aminobutyric Acid; Glutamate Decarboxylase; Pentobarbital; Diazepam;

Mesh terms: Animals; Anti-Anxiety Agents/pharmacology; Anxiety/genetics; Crosses, Genetic; Diazepam/pharmacology; Female; Glutamate Decarboxylase/deficiency; Isoenzymes/deficiency; Male; Maze Learning/drug effects; Mice; Mice, Inbred C57BL; Mice, Knockout; Pentobarbital/pharmacology; Receptors, GABA-A/physiology; Reflex/drug effects; gamma-Aminobutyric Acid/physiology;

Citations: - 9822384

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