Aberrant Purkinje cell activity is the cause of @entity3519 in a shRNA-based @entity19 model of XXXX .

@entity1 @entity3520 @entity304 @entity19 @entity1372 @entity17558 @entity76 @entity3519 @entity21 @entity7832
UNASSIGNED: Loss-of-function mutations in the a3 isoform of the @entity1372 pump are responsible for @entity17558 ( @entity17558 ). A pharmacologic model of @entity17558 replicates the most salient features of @entity17558 , and implicates both the cerebellum and basal @entity21 ; @entity3519 is associated with @entity76 , and the @entity304 -like features are attributable to the basal ganglia. The pharmacologic agent used to generate the model, @entity7832 , is selective for @entity1372 pumps. However, close to the infusion sites in vivo it likely affects all @entity1372 pump isoforms. Therefore, it remains to be established whether selective loss of a3-containing @entity1372 pumps replicates the pharmacologic model. Moreover, while the pharmacologic model suggested that aberrant firing of Purkinje cells was the main cause of @entity76 , it did not allow the scrutiny of this hypothesis. To address these questions RNA interference using small hairpin RNAs (shRNAs) delivered via adeno-associated viruses (AAV) was used to specifically knockdown a3-containing @entity1372 pumps in different regions of the adult @entity19 brain. Knockdown of the a3-containing @entity1372 pumps mimicked both the behavioral and electrophysiological changes seen in the pharmacologic model of @entity17558 , recapitulating key aspects of the @entity1 disorder. Further, we found that knockdown of the a3 isoform altered the intrinsic pacemaking of Purkinje cells, but not the neurons of the @entity76 . Therefore, acute knockdown of proteins associated with @entity3520 may be a good strategy for developing phenotypic genetic @entity19 models where traditional transgenic models have failed to produce symptomatic @entity19 .
