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, 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.
Kash
S F
SF
Departments of Medicine and Microbiology/Immunology, and Hormone Research Institute, University of California, San Francisco, CA 94143, USA.
Tecott
L H
LH
Hodge
C
C
Baekkeskov
S
S
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000235:genetics*; D003433:Crosses, Genetic; D003975:Diazepam / Q000494:pharmacology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010424:Pentobarbital / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000502:physiology; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology