UNCOUPLING OF GABA(A) BENZODIAZEPINE RECEPTOR ALPHA(1), BETA(2), AND GAMMA(2) SUBUNIT MESSENGER-RNA EXPRESSION IN CEREBELLAR PURKINJE-CELLSOF STAGGERER MUTANT MICE

The mammalian GABA(A)/benzodiazepine (GAB(A)/BZ) receptor is comprised of several subunit isoforms: alpha(1-5), beta(1-3), gamma(1-3), and d elta. In the present studies, the expression of alpha(1), beta(2), and gamma(2) subunit mRNAs was examined in cerebellar Purkinje cells and deep cerebellar neurons of staggerer mutant mice during postnatal deve lopment. In control animals, the three subunit mRNAs were present at h igh density in Purkinje cells which, in adult animals, form a monolaye r at the interface of the granule cell and molecular layers. The numbe r of Purkinje cells in the staggerer cerebellar cortex is reduced; the majority of those that remain are retained within the granule cell la yer and are unable to receive normal afferent synapses from granule ce lls. The three subunit mRNAs were expressed at similar levels in both staggerer and control Purkinje cells until postnatal day 9. After this time, although the alpha(1) subunit mRNA was maintained at control le vels in staggerer Purkinje cells, the expression of beta(2) and gamma( 2) subunit mRNAs decreased, and was largely absent by postnatal day 20 . The loss of beta(2) and gamma(2) mRNA expression in staggerer was sp ecific to Purkinje cells, since all three mRNAs were present throughou t postnatal development in other brain regions, including the deep cer ebellar nuclei. The present studies indicate that in cerebellar Purkin je cells, the GAPA(A)/BZ receptor alpha(1), and beta(2) and gamma(2), subunit mRNAs are regulated by distinct mechanisms which are different ially affected by the staggerer mutation.