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

Abstract

The larger isoform of the enzyme glutamate decarboxylase, GAD67, synthesizes >90% of basal levels of ␥-aminobutyric acid (GABA) in the brain. In contrast, the smaller isoform, GAD65, has been implicated in the finetuning 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.

Increased Vulnerability to Depressive-Like Behavior of Mice with Decreased Expression of VGLUT1

“…Moreover, mice lacking an isoform of GAD65 have shown reduced GABA levels and increased anxiety (46,47) while rats exposed to CMS show reduced GABA levels, anhedonia and helplessness (48,49). We suggest that the downregulation of VGAT and its coupled GABA synthesising enzyme GAD65 in response to CMS could explain the decreased GABA levels observed in the frontal cortex and in the hippocampus of the CMS mice.…”

Long-term effects of culture of preimplantation mouse embryos on behavior

“…The elevated zero maze relies on the fact that rodents are apprehensive in both open and elevated areas and, therefore, prefer to spend the majority of their time in enclosed areas (16). Culture-derived animals spent more time in the open quadrant than in vivo-derived animals, suggesting alterations in anxiety as a result of embryo culture (Fig.…”

“…Anxiety can be assayed by using the elevated zero maze or elevated plus maze, rodent behavioral tests that have been used successfully to isolate novel anti-anxiety drugs with actions similar to valium (16). The elevated zero maze relies on the fact that rodents are apprehensive in both open and elevated areas and, therefore, prefer to spend the majority of their time in enclosed areas (16).…”

“…Anxiety was measured by using the elevated zero maze test as described (16). Briefly, to begin each trial, mice were placed in the center of a closed quadrant of the circular maze and were allowed to explore the maze for 5 min; all mice were started in the same closed quadrant of the maze.…”

“…Immediately after collecting the in vivo-derived blastocysts, these embryos were combined with equal numbers (usually five to six) of fully expanded Whitten's medium-and KSOM-cultured blastocysts. These pooled zona pellucida-intact embryos (15)(16)(17)(18) were then transferred to the uterine horns of a pseudopregnant foster mother according to standard procedures (15). In each experiment, the transgene was assigned to a different group to minimize the possibility that any observed effect was due to the transgene.…”