Effect of unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway on GABA(A) receptor subunit gene expression in the rodent basal ganglia and thalamus

In Parkinson's disease, changes in GABAergic activity occurring downstream of the striatal dopamine loss are accompanied by reciprocal changes in GABA (A) receptor binding, the underlying molecular mechanisms for which are unk nown. This study examined whether changes in expression of the genes encodi ng known GABA(A) receptor subunits (alpha(1-4), beta(1-3), gamma(1-3) and d elta) could account for this receptor plasticity using a rodent model of Pa rkinson's disease with a 6-hydroxydopamine-induced nigrostriatal lesion. An alysis of autoradiograms of the basal ganglia and thalamus revealed changes in expression of only four of the 11 subunits studied. Expression of alpha (1) and beta(2) subunit genes was altered in a parallel manner following a 6-hydroxydopamine lesion; messenger RNA levels for both were significantly increased in the substantia nigra pars reticulata (11 +/- 4% and 17 +/- 1%, respectively), and significantly reduced in the globus pallidus (18 +/- 3% and 16 +/- 3%, respectively) and parafascicular nucleus (19 +/- 3% and 16 +/- 5%, respectively). Smaller changes in the messenger RNA levels encoding the al subunit in the lateral amygdala (8 +/- 1% decrease) and the alpha(4 ) and gamma(2) subunits in the striatum (10 +/- 2% and 6 +/- 1% increase, r espectively) were also observed. No changes in expression were noted for an y other subunits in any region studied. Clearly, both region- and subunitsp ecific regulation of GABA(A) receptor subunit gene expression occurs follow ing a nigrostriatal tract lesion. The changes in expression of the alpha(1) and beta(2) subunit genes probabl y contribute to the documented changes in GABA(A) receptor binding followin g striatal dopamine depletion. Moreover, they provide a molecular basis by which the pathological changes in GABAergic activity in Parkinson's disease may be partially compensated. (C) 1999 IBRO. Published by Elsevier Science Ltd.