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

The larger isoform of the enzyme glutamate decarboxylase, GAD67, synthesize s >90% of basal levels of gamma-aminobutyric acid (GABA) in the brain. In c ontrast, the smaller isoform, GAD65, has been implicated in the fine-tuning of inhibitory neurotransmission. Mice deficient in GBD65 exhibit increased anxiety-like responses in both the open field and elevated zero maze assay s. Additionally, GAD65-deficient mice have a diminished response to the anx iolytics diazepam and pentobarbital, both of which interact with GABA-A rec eptors in a GABA-dependent fashion to facilitate GABAergic neurotransmissio n. Loss of GAD65-generated GABA does not appear to result in compensatory p ostsynaptic GABA-A receptor changes based on radioligand receptor binding s tudies, which revealed no change in the postsynaptic GABA-A receptor densit y. Furthermore, mutant and wild-type animals do not differ in their behavio ral response to muscimol, which acts independently of the presence of GABA. me propose that stress-induced GABA release is impaired in GAD65-deficient mice, resulting in increased anxiety-like responses and a diminished respo nse to the acute effects of drugs that facilitate the actions of released G ABA.