Removal of GABAA Receptor γ2 Subunits from Parvalbumin Neurons Causes Wide-Ranging Behavioral Alterations

We investigated the behavioral significance of fast synaptic inhibition by alpha beta gamma 2-type GABA(A) receptors on parvalbumin (Pv) cells. The GABA(A) receptor gamma 2 subunit gene was selectively inactivated in Pv-positive neurons by Cre/loxP recombination. The resulting Pv-Delta gamma 2 mice were relatively healthy in the first postnatal weeks; but then as Cre started to be expressed, the mice progressively developed wide-ranging phenotypic alterations including low body weight, motor deficits and tremor, decreased anxiety levels, decreased pain sensitivity and deficient prepulse inhibition of the acoustic startle reflex and impaired spatial learning. Nevertheless, the deletion was not lethal, and mice did not show increased mortality even after one year. Autoradiography with t-butylbicyclophosphoro[S-35]thionate suggested an increased amount of GABA(A) receptors with only alpha and beta subunits in central nervous system regions that contained high levels of parvalbumin neurons. Using BACtransgenesis, we reduced some of the Pv-Delta gamma 2 phenotype by selectively re-expressing the wild-type gamma 2 subunit back into some Pv cells (reticular thalamic neurons and cerebellar Pv-positive neurons). This produced less severe impairments of motor skills and spatial learning compared with Pv-Delta gamma 2 mice, but all other deficits remained. Our results reveal the widespread significance of fast GABAergic inhibition onto Pv-positive neurons for diverse behavioral modalities, such as motor coordination, sensorimotor integration, emotional behavior and nociception.