title: The GAD65 knock out mouse - a model for GABAergic processes in fear- and stress-induced psychopathology.
abstract: The γ-amino butyric acid (GABA) synthetic enzyme glutamic acid decarboxylase (GAD)65 is critically involved in the activity-dependent regulation of GABAergic inhibition in the central nervous system. It is also required for the maturation of the GABAergic system during adolescence, a phase that is critical for the development of several neuropsychiatric diseases. Mice bearing a null mutation of the GAD65 gene develop hyperexcitability of the amygdala and hippocampus, and a phenotype of increased anxiety and pathological fear memory reminiscent of posttraumatic stress disorder. Although genetic association of GAD65 in human has not yet been reported, these findings are in line with observations of reduced GABAergic function in these brain regions of anxiety disorder patients. The particular value of GAD65(-/-) mice thus lies in modeling the effects of reduced GABAergic function in the mature nervous system. The expression of GAD65 and a second GAD isozyme, GAD67, are differentially regulated in response to stress in limbic brain areas suggesting that by controlling GABAergic inhibition these enzymes determine the vulnerability for the development of pathological anxiety and other stress-induced phenotypes. In fact, we could recently show that GAD65 haplodeficiency, which results in delayed postnatal increase of GABA levels, provides resilience to juvenile-stress-induced anxiety to GAD65(+/-) mice thus foiling the increased fear and anxiety in homozygous GAD65(-/-) mice.
authors.affiliation: Department of Genetics & Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Müller
authors.forename: Gürsel
authors.initials: G
authors.lastname: Çalışkan
authors.forename: Oliver
authors.initials: O
authors.lastname: Stork
mesh_terms: D000679:Amygdala / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001008:Anxiety Disorders / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005239:Fear; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D013315:Stress, Psychological / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2
keywords: Anxiety; GAD65; GAD67; epilepsy; fear; knock out mouse; memory; panic disorder; posttraumatic stress disorder; schizophrenia