Sf. Kash et al., Increased anxiety and altered responses to anxiolytics in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase, P NAS US, 96(4), 1999, pp. 1698-1703
Citations number
49
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
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.