title: Effect of unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway on GABA(A) receptor subunit gene expression in the rodent basal ganglia and thalamus.
abstract: 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 unknown. This study examined whether changes in expression of the genes encoding known GABA(A) receptor subunits (alpha(1-4), beta(1-3), gamma(1-3) and delta) could account for this receptor plasticity using a rodent model of Parkinson's disease with a 6-hydroxydopamine-induced nigrostriatal lesion. Analysis of autoradiograms of the basal ganglia and thalamus revealed changes in expression of only four of the 11 subunits studied. Expression of alpha1 and beta2 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 alpha1 subunit in the lateral amygdala (8 +/- 1% decrease) and the alpha4 and gamma2 subunits in the striatum (10 +/- 2% and 6 +/- 1% increase, respectively) were also observed. No changes in expression were noted for any other subunits in any region studied. Clearly, both region- and subunit-specific regulation of GABA(A) receptor subunit gene expression occurs following a nigrostriatal tract lesion. The changes in expression of the alpha1 and beta2 subunit genes probably contribute to the documented changes in GABA(A) receptor binding following 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.
authors.affiliation: Centre for Age-Related Diseases, Guy's, King's and St Thomas' School of Biomedical Sciences, King's College London, Guy's Campus, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Chadha
authors.forename: L G
authors.initials: LG
authors.lastname: Dawson
authors.forename: P G
authors.initials: PG
authors.lastname: Jenner
authors.forename: S
authors.initials: S
authors.lastname: Duty
mesh_terms: D000818:Animals; D001345:Autoradiography; D001479:Basal Ganglia / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D015870:Gene Expression; D008297:Male; D008454:Mazindol / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects / Q000473:pathology; D016627:Oxidopamine / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics*; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D013788:Thalamus / Q000502:physiology*; D014018:Tissue Distribution
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D016627:Oxidopamine; D008454:Mazindol