MODULATION OF RAT ROTATIONAL BEHAVIOR BY DIRECT GENE-TRANSFER OF CONSTITUTIVELY ACTIVE PROTEIN-KINASE-C INTO NIGROSTRIATAL NEURONS

The modulation of motor behavior by protein kinase C (PKC) signaling p athways in nigrostriatal neurons was examined by using a genetic inter vention approach. Herpes simplex virus type 1 (HSV-1) vectors that enc ode a catalytic domain of rat PKC beta II (Pkc Delta) were developed. Pkc Delta exhibited a constitutively active protein kinase activity wi th a substrate specificity similar to that of rat brain PKC. As demons trated in cultured sympathetic neurons, Pkc Delta caused a long-lastin g, activation-dependent increase in neurotransmitter release. In the r at brain, microinjection of HSV-1 vectors that contain the tyrosine hy droxylase promoter targeted expression to dopaminergic nigrostriatal n eurons. Expression of pkc Delta in a small percentage of nigrostriatal neurons (similar to 0.1-2%) was sufficient to produce a long-term (gr eater than or equal to 1 month) change in apomorphine-induced rotation al behavior. Nigrostriatal neurons were the only catecholaminergic neu rons that contained Pkc Delta, and the amount of rotational behavior w as correlated with the number of affected nigrostriatal neurons. The c hange in apomorphine-induced rotational behavior was blocked by a dopa mine receptor antagonist (fluphenazine). D-2-like dopamine receptor de nsity was increased in those regions of the striatum innervated by the affected nigrostriatal neurons. Therefore, this strategy enabled the demonstration that a PKC pathway or PKC pathways in nigrostriatal neur ons modulate apomorphine-induced rotational behavior, and altered dopa minergic transmission from nigrostriatal neurons appears to be the aff ected neuronal physiology responsible for the change in rotational beh avior.