GABAergic

Endogenous GABA levels were altered in mice by targeting the two isoforms of glutamic acid dehydrogenase (GAD) responsible for the synthesis of GABA. Mice lacking GAD67, which is thought to be responsible for maintenance of basal GABA levels, produced a prenatal lethal phenotype. Deletion of the GAD65 gene, thought to be activated in response to high endogenous GABA demand, reduced GABA levels, was associated with a lower rate of lethality than the GAD67 mutant mice, and exhibited an increase in anxiety-like behavior in the elevated zero maze and open field tests.22

Deletion of the b2 subunit gene of the GABAa receptor decreased the total number of GABAa receptors in the brain, but did not produce any clear anxiety-related phenotype.23 Mice deficient in both splice variants of the g2 subunit (g2S, g2L) of the GABAa receptor were insensitive to either the behavioral or electrophysiological effects of benzodiazepines.24 Homozygous mutants failed to survive past postnatal day 18, and behavioral testing with heterozygote g2 mutants showed anxiogenic-like behavior in the open field, elevated plus maze (EPM), and light/dark box tests.24 Although the g2 subunit knockout mice showed some increases in anxiety-like behavior, transgenic mice overexpressing either the g2S or g2L subunits of the GABAA receptor failed to exhibit any anxiety-like phenotype when compared to the responses of their wild-type littermate controls.25

Conquering Fear In The 21th Century

Conquering Fear In The 21th Century

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