Partial restoration of striatal GABA(A) receptor balance by functional mesencephalic dopaminergic grafts in mice with hereditary parkinsonism

Levels of inhibitory amino acid receptors were studied in the weaver (wv/wv ) mouse model of dopamine (DA) deficiency after unilateral intrastriatal tr ansplantation of fetal mesencephalic cell suspensions. Graft integration wa s verified by turning behavior tests and from the topographical levels of t he DA transporter, tagged autoradiographically with 3 nM [H-3]GBR 12935. Th e average increase in [H-3]GBR 12935 binding in grafted dorsal striatum com pared to nongrafted wv/wv striatum was 60% 3 months after grafting. Autorad iography of 8 nM [H-3]flunitrazepam and 12 nM [H-3]muscimol binding was car ried out to visualize the distribution of GABA(A) receptors in +/+ mice and in recipient weaver mutants. A 17% increase in [H-3]flunitrazepam binding and a 20% increase in [H-3]muscimol binding was found in the nongrafted dor sal striatum of weaver mutants compared to +/+. The functional mesencephali c grafts had a partial normalizing effect on both [H-3]flunitrazepam and [H -3]muscimol binding in the dorsal striatum of the weaver recipients. The no rmalization brought about by the grafts was around 20% for [H-3]flunitrazep am binding and more than 40% for [H-3]muscimol binding. The results are dis cussed in the context of the important interaction between the converging g lutamatergic corticostriatal and DAergic nigrostriatal pathways in controll ing the functional GABAergic output of the basal ganglia in Parkinson's dis ease and in experimental models of DA deficiency. (C) 1999 Academic Press.