Decreased expression of GABAA receptor alpha6 and beta3 subunits in stargazer mutant mice: a possible role for brain-derived neurotrophic factor in the regulation of cerebellar GABAA receptor expression?
The cerebellar granule cells of the spontaneous recessive mutant mouse strain, stargazer (stg/stg), fail to express brain-derived neurotrophic factor mRNA. This deficit is exclusive to these neurons and is believed to underlie the motor irregularities displayed by stg/stg, though the molecular basis for their phenotype has still to be resolved. Brain-derived neurotrophic factor has been shown to play a role in the postnatal maturation of cerebellar granule cells. Differentiation of these neurons, postnatally, is characterised by a switch in their GABAA receptor subunit expression profile. Notably, the GABAA receptor alpha6 subunit, which is specific to these neurons, becomes detectable at postnatal days 10-14 (P10-14). To determine whether cerebellar GABAA receptor expression has been compromised in stg/stg mice, the expression levels of GABAA receptor alpha1, alpha6, beta2 and beta3 subunits were compared between stg/stg mice and the appropriate wild-type background strain, C57BL/6J (+/+). By quantitative immunoblotting, it was found that the expression of the alpha6 and beta3 subunits was 23+/-8% and 38+/-12% (mean+/-S.E.M., n=6) of control (+/+) levels, respectively. In contrast, the expression of the alpha1 and beta2 subunits was not significantly different from controls, being 116+/-11% and 87+/-24% (mean+/-S.E.M., n=6) of +/+ levels, respectively. Total specific [3H]Ro15-4513 binding activity detected in cerebellar membranes prepared from stg/stg was not significantly different from +/+ mice. However, the benzodiazepine agonist-insensitive subtype of [3H]Ro15-4513 binding activity, a pharmacological motif of alpha6 subunit-containing GABAA receptors, was lower in stg/stg mice relative to the +/+ strain which correlated with the lowered level of alpha6 subunit expression. Thus, we have identified an abnormality in the GABAA receptor profile of stg/stg mutant mice that might underpin its irregular phenotype.[1]References
- Decreased expression of GABAA receptor alpha6 and beta3 subunits in stargazer mutant mice: a possible role for brain-derived neurotrophic factor in the regulation of cerebellar GABAA receptor expression? Thompson, C.L., Tehrani, M.H., Barnes, E.M., Stephenson, F.A. Brain Res. Mol. Brain Res. (1998) [Pubmed]
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