PROLINE-RICH TRANSMEMBRANE PROTEIN 2 KNOCK-IN MICE PRESENT NIGROSTRIATAL DOPAMINERGIC HYPERACTIVITY AND INCREASED SUSCEPTIBILITY TO L-DOPA-INDUCED MOTOR DEFICITS

Abstract Mutations of proline-rich transmembrane protein 2 (PRRT2) lead to dyskinetic and convulsive disorders such as paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile seizure and hemiplegic migraine. PKD is characterized by attacks of involuntary movements precipitated by suddenly initiated motion. Previous studies have shown that PKD might be caused by cerebellar dysfunction; however, considering widespread expression of Prrt2 in the whole brain, it is likely that some other motor-related regions including the basal ganglia, where dopaminergic neurons are most abundant in the brain, might also be a part of pathogenesis of PKD. Here, we generated Prrt2 knock-in (KI) mice harboring mutation c.672dupG that mimics the human pathological mutation c.649dupC and investigated the role of Prrt2 in the basal ganglia. The mutant transcript and protein were abolished within the striatum, confirming loss-of-function nature of PKD and related disorders. Importantly, intrastriatal microdialysis revealed that the Prrt2 mutation dramatically elevated extracellular dopamine levels during the depolarized state, which might result from the increase in dopamine release because pharmacological inhibition of dopamine reuptake produced a greater elevation of extracellular dopamine levels in Prrt2-KI mice than in wild-type mice. Moreover, administration of L-dopa, a precursor of dopamine, exacerbated rotarod performance of Prrt2-KI mice more severely than that of wild-type mice. Overall, these findings suggest that dopaminergic dysfunction within the basal ganglia by the PRRT2 mutation might be implicated in a part of motor symptoms of PKD and related disorders.