Title | Abnormal high-frequency burst firing of cerebellar neurons in rapid-onset dystonia-parkinsonism. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Fremont R, D Calderon P, Maleki S, Khodakhah K |
Journal | J Neurosci |
Volume | 34 |
Issue | 35 |
Pagination | 11723-32 |
Date Published | 2014 Aug 27 |
ISSN | 1529-2401 |
Keywords | Animals, Cerebellum, Disease Models, Animal, Dystonic Disorders, Electrophysiology, Male, Mice, Mice, Inbred C57BL, Purkinje Cells, Rats, Rats, Wistar, Sodium-Potassium-Exchanging ATPase |
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. |
DOI | 10.1523/JNEUROSCI.1409-14.2014 |
Alternate Journal | J Neurosci |
PubMed ID | 25164667 |
PubMed Central ID | PMC4145175 |
Grant List | R01 NS079750 / NS / NINDS NIH HHS / United States F30 NS071665 / NS / NINDS NIH HHS / United States R01 NS050808 / NS / NINDS NIH HHS / United States S10 RR027888 / RR / NCRR NIH HHS / United States T32 GM007288 / GM / NIGMS NIH HHS / United States |