DECREASED EXPRESSION OF GABA(A) RECEPTOR ALPHA-6 AND BETA-3 SUBUNITS IN STARGAZER MUTANT MICE - A POSSIBLE ROLE FOR BRAIN-DERIVED NEUROTROPHIC FACTOR IN THE REGULATION OF CEREBELLAR GABA(A) RECEPTOR EXPRESSION

The cerebellar granule cells of the spontaneous recessive mutant mouse strain, stargazer (stg/stg), fail to express brain-derived neurotroph ic factor mRNA. This deficit is exclusive to these neurons and is beli eved to underlie the motor irregularities displayed by stg/stg, though the molecular basis for their phenotype has still to be resolved. Bra in-derived neurotrophic factor has been shown to play a role in the po stnatal maturation of cerebellar granule cells. Differentiation of the se neurons, postnatally, is characterised by a switch in their GABA(A) receptor subunit expression profile. Notably, the GABA(A) receptor al pha 6 subunit, which is specific to these neurons, becomes detectable at postnatal days 10-14 (P10-14). To determine whether cerebellar GABA (A) receptor expression has been compromised in stg/stg mice, the expr ession levels of GABA(A) receptor alpha 1, alpha 6, beta 2 and beta 3 subunits were compared between stg/stg mice and the appropriate wild-t ype background strain, C57BL/6J (+ / +). By quantitative immunoblottin g, it was found that the expression of the alpha 6 and beta 3 subunits was 23 +/- 8% and 38 +/- 12% (mean +/- S.E.M., n = 6) of control (+ / +) levels, respectively. In contrast, the expression of the alpha 1 a nd beta 2 subunits was not significantly different from controls, bein g 116 +/- 11% and 87 +/- 24% (mean +/- S.E.M., n = 6) of +/+ levels, r espectively. Total specific [H-3]Ro15-4513 binding activity detected i n cerebellar membranes prepared from stg/stg was not significantly dif ferent from +/+ mice. However, the benzodiazepine agonist-insensitive subtype of [H-3]Ro15-4513 binding activity, a pharmacological motif of alpha 6 subunit-containing GABA(A) receptors, was lower in stg/stg mi ce relative to the +/+ strain which correlated with the lowered level of alpha 6 subunit expression. Thus, we have identified an abnormality in the GABA(A) receptor profile of stg/stg mutant mice that might und erpin its irregular phenotype. (C) 1998 Elsevier Science B.V. All righ ts reserved.