MICE LACKING THE 65 KDA ISOFORM OF GLUTAMIC-ACID DECARBOXYLASE (GAD65) MAINTAIN NORMAL LEVELS OF GAD67 AND GABA IN THEIR BRAINS BUT ARE SUSCEPTIBLE TO SEIZURES

The gene encoding of the 65 kDa isoform of the gamma-aminobutyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase (GAD), GAD65, was targeted in mice by homologous recombination. Viable GAD65 -/- mi ce were obtained with the expected mendelian frequency and displayed n o gross morphological defects. Despite the complete loss of GAD65 mRNA and protein in a homozygous mutant, there was no difference in GABA c ontent in the brains of GAD65 +/+, +/-, and -/- mice. As for che other 67 kDa isoform (GAD67), the levels of mRNA and protein were largely u nchanged by the GAD65 mutation. General behavior, including locomotor activity and performance in the Morris water maze task, appeared norma l, bur seizures were more easily induced by picrotoxin and pentylenete trazol: the latencies to seizures induced by picrotoxin were shorter a nd the dose of pentylenetetrazol required for induction of seizures wa s lower. (C) 1996 Academic Press.