title: Abnormal high-frequency burst firing of cerebellar neurons in rapid-onset dystonia-parkinsonism.
abstract: Loss-of-function mutations in the α3 isoform of the Na(+)/K(+) ATPase (sodium pump) are responsible for rapid-onset dystonia parkinsonism (DYT12). Recently, a pharmacological model of DYT12 was generated implicating both the cerebellum and basal ganglia in the disorder. Notably, partially blocking sodium pumps in the cerebellum was necessary and sufficient for induction of dystonia. Thus, a key question that remains is how partially blocking sodium pumps in the cerebellum induces dystonia. In vivo recordings from dystonic mice revealed abnormal high-frequency bursting activity in neurons of the deep cerebellar nuclei (DCN), which comprise the bulk of cerebellar output. In the same mice, Purkinje cells, which provide strong inhibitory drive to DCN cells, also fired in a similarly erratic manner. In vitro studies demonstrated that Purkinje cells are highly sensitive to sodium pump dysfunction that alters the intrinsic pacemaking of these neurons, resulting in erratic burst firing similar to that identified in vivo. This abnormal firing abates when sodium pump function is restored and dystonia caused by partial block of sodium pumps can be similarly alleviated. These findings suggest that persistent high-frequency burst firing of cerebellar neurons caused by sodium pump dysfunction underlies dystonia in this model of DYT12.
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Rachel
authors.initials: R
authors.lastname: Fremont
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: D Paola
authors.initials: DP
authors.lastname: Calderon
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Sara
authors.identifier: http://orcid.org/0000-0002-1489-1145
authors.initials: S
authors.lastname: Maleki
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461 K.khodakhah@einstein.yu.edu.
authors.forename: Kamran
authors.initials: K
authors.lastname: Khodakhah
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000503:physiopathology*; D004195:Disease Models, Animal; D020821:Dystonic Disorders / Q000503:physiopathology*; D004594:Electrophysiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011689:Purkinje Cells / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology*
chemical_list: D000254:Sodium-Potassium-Exchanging ATPase
keywords: basal ganglia; cerebellum