Deficit of striatal parvalbumin-reactive GABAergic interneurons and decreased basal ganglia output in a genetic rodent model of idiopathic paroxysmaldystonia

The underlying mechanisms of various types of hereditary dystonia, a common movement disorder, are still unknown. Recent findings in a genetic model o f a type of paroxysmal dystonia, the dt sz mutant hamster, pointed to stria tal dysfunctions. In the present study, immunhistochemical experiments demo nstrated a marked decrease in the number and density of parvalbumin-immunor eactive GABAergic interneurons in all striatal subregions of mutant hamster s. To examine the functional relevance of the reduction of these inhibitory interneurons, the effects of the GABA(A) receptor agonist muscimol on seve rity of dystonia were examined after microinjections into the striatum and after systemic administrations. Muscimol improved the dystonic syndrome aft er striatal injections to a similar extent as after systemic treatment, sup porting the importance of the deficiency of striatal GABAergic interneurons for the occurrence of the motor disturbances. The disinhibition of striata l GABAergic projection neurons, as suggested by recent extracellular single -unit recordings in dt(sz) hamsters, should lead to an abnormal neuronal ac tivity in the basal ganglia output nuclei. Indeed, a significantly decrease d basal discharge rate of entopeduncular neurons was found in dt(sz) hamste rs. We conclude that a deficit of striatal GABAergic interneurons leads by disinhibition of striatal GABAergic projection neurons to a reduced activit y in the entopeduncular nucleus, i.e., to a decreased basal ganglia output. This finding is in line with the current hypothesis about the pathophysiol ogy of hyperkinesias. The results indicate that striatal interneurons deser ve attention in basic and clinical research of those movement disorders.