Selective modulation of basal ganglia circuits

Parkinson's Disease (PD) is a neuro-degenerative disorder of the basal ganglia in which there is a loss of dopamine-containing neurons in the substantia nigra, which project to the putamen and caudate (striatum). When the loss of dopaminergic innervation in the striatum reaches a critical level, motor symptoms such as tremor, rigidity, and brady kinesia become manifest. The availability of animal models of PD have led to a heightened understanding of the basal circuitry, and underscored the importance of neuronal activity in two parallel striatal outflow pathways termed the "direct" and "indirect" pathway. The relative activity of the pathways is disturbed in the Parkinsonian state. This proposal explores novel techniques aimed at differentially controlling activity in these two pathways using gene transfer vectors that alter neuronal excitability. Viral vectors based on herpes virus or adenovirus will be constructed and used to augment the voltage-gated potassium channel activity in cultured striatal neurons from rat. Single-cell electrophysiology and immunocytochemistry will be used to monitor the effects of this channel modulation on defined cell types corresponding to the direct or indirect pathway. The specific aims of this proposal are: (1) to determine whether of a useful model system of basal ganglia circuitry can be developed using dispersed primary cultures of rat putaminal neurons; (2) to determine whether viral gene transfer vectors using cell-specific promoters are capable of selectively transducing cells belonging to the indirect or direct putaminal output pathways, and (3) to develop and test a gene transfer vector designed to selectively augment K+ channel activity in basal ganglia neurons belonging to either the direct or indirect output pathways. Successful completion of this proposal would allow further the development of a gene therapy for the symptomatic treatment of PD.