Normal electrophysiological and behavioral responses to ethanol in mice lacking the long splice variant of the gamma 2 subunit of the gamma-aminobutyrate type A receptor

The gamma subunit of the gamma-aminobutyric acid type A receptor (GABA(A)-R ) is essential for bestowing both normal single channel conductance and sen sitivity to benzodiazepines on native GABA(A)-Rs. The long splice variant o f the gamma 2 subunit (gamma 2L) has been postulated to be essential in med iating the modulatory actions of ethanol at the GABA(A)-R. In order to eval uate this hypothesis, gene targeting was used to delete the 24bp exon which distinguishes gamma 2L from the short splice variant (gamma 2S). Mice homo zygous for this exon deletion (gamma 2L(-/-)) are viable and indistinguisha ble from wild-type (gamma 2L(+/+)) mice. No gamma 2L mRNA was detected in t hese mice, nor could gamma 2L-containing GABA(A)-R protein be detected by s pecific antibodies. Radioligand binding studies showed the total amount of gamma 2 subunit protein to be not significantly changed, suggesting that ga mma 2S replaces gamma 2L in the brains of the knockout animals. Electrophys iological recordings from dorsal root ganglion neurons revealed a normal co mplement of functional receptors. There was no difference in the potentiati on of GABA currents by ethanol (20-200 mM) observed in neurons from gamma 2 L(+/+) or gamma 2L(-/-) mice. Several behavioral effects of ethanol, such a s sleep time, anxiolysis, acute functional tolerance, chronic withdrawal hy perexcitability and hyperlocomotor activity were also unaffected by genotyp e. It is concluded that gamma 2L is not required for ethanol's modulatory a ction at the GABA(A)-R or whole animal behavioral effects. (C) 1999 Elsevie r Science Ltd. All rights reserved.