Partial Restoration of Striatal GABAA Receptor Balance by Functional Mesencephalic Dopaminergic Grafts in Mice with Hereditary Parkinsonism

Abstract Levels of inhibitory amino acid receptors were studied in the weaver ( wv/wv ) mouse model of dopamine (DA) deficiency after unilateral intrastriatal transplantation of fetal mesencephalic cell suspensions. Graft integration was verified by turning behavior tests and from the topographical levels of the DA transporter, tagged autoradiographically with 3 nM [ 3 H]GBR 12935. The average increase in [ 3 H]GBR 12935 binding in grafted dorsal striatum compared to nongrafted wv/wv striatum was 60% 3 months after grafting. Autoradiography of 8 nM [ 3 H]flunitrazepam and 12 nM [ 3 H]muscimol binding was carried out to visualize the distribution of GABA A receptors in +/+ mice and in recipient weaver mutants. A 17% increase in [ 3 H]flunitrazepam binding and a 20% increase in [ 3 H]muscimol binding was found in the nongrafted dorsal striatum of weaver mutants compared to +/+. The functional mesencephalic grafts had a partial normalizing effect on both [ 3 H]flunitrazepam and [ 3 H]muscimol binding in the dorsal striatum of the weaver recipients. The normalization brought about by the grafts was around 20% for [ 3 H]flunitrazepam binding and more than 40% for [ 3 H]muscimol binding. The results are discussed in the context of the important interaction between the converging glutamatergic corticostriatal and DAergic nigrostriatal pathways in controlling the functional GABAergic output of the basal ganglia in Parkinson's disease and in experimental models of DA deficiency.