A number of neurologic disorders are episodic. The subjects suffering from these disorders have relatively few symptoms in between episodes. Yet they sporadically suffer from severe neurologic attacks which last from minutes to hours. These disorders include migraine, episodic ataxia, and paroxysmal dyskinesia. The episodes are often triggered by factors such as emotional or physical stress, or by ingestion of relatively harmless doses of caffeine and ethanol. Episodic ataxia type 2 (EA2), a hereditary ataxia caused by mutations in the P/Q-type calcium channels, is one such disorder. During the past funding period we provided good evidence in support of the hypothesis that the baseline ataxia seen in EA2 is likely caused by the loss of precision of pacemaking in cerebellar Purkinje cells. We were also able to offer a number of rational pharmacologic therapeutic approaches to restore the precision of pacemaking and lessen ataxia. In this proposal we seek to invest our efforts in unraveling the mechanisms that contribute to episodes of severe ataxia and dyskinesia in EA2. Using well established mouse models of EA2 we wish to test the hypothesis that all three triggers (stress, caffeine and ethanol) cause attacks by converging onto Purkinje cells and transforming their regular activity to highly erratic burst firing. Our working hypothesis is that his transformation is mediated by norepinephrine which increases CK2 dependent phosphorylation of Purkinje cell SK channels. Once phosphorylated, the SK conductance is reduced thereby promoting Purkinje cell burst firing. We will test our working hypothesis using a combination of techniques including behavioral assessment of motor (dys)function, and single cell recordings in acutely dissociated neurons, the brain slice preparation, and in vivo in awake animals.

Public Health Relevance

A number of neurologic disorders are episodic. The subjects suffering from these disorders have relatively few symptoms in between episodes. Yet they sporadically suffer from severe neurologic attacks which last from minutes to hours. These disorders include migraine, episodic ataxia, and paroxysmal dyskinesia. The episodes are often triggered by factors such as emotional or physical stress, or by ingestion of relatively harmless doses of caffeine and ethanol. Episodic ataxia type 2 (EA2), the most common episodic hereditary ataxia, is one such disorder. In this proposal we seek to delineate the mechanism and signaling pathways that mediate the episodic attacks of ataxia and dyskinesia in EA2.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050808-08
Application #
8876821
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gwinn, Katrina
Project Start
2012-09-15
Project End
2015-08-31
Budget Start
2015-06-01
Budget End
2015-08-31
Support Year
8
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Kros, Lieke; Angueyra Aristizábal, Chantal A; Khodakhah, Kamran (2018) Cerebellar involvement in migraine. Cephalalgia 38:1782-1791
Tara, Esra; Vitenzon, Ariel; Hess, Ellen et al. (2018) Aberrant cerebellar Purkinje cell activity as the cause of motor attacks in a mouse model of episodic ataxia type 2. Dis Model Mech 11:
Shakkottai, Vikram G; Batla, Amit; Bhatia, Kailash et al. (2017) Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia. Cerebellum 16:577-594
Strupp, Michael; Teufel, Julian; Zwergal, Andreas et al. (2017) Aminopyridines for the treatment of neurologic disorders. Neurol Clin Pract 7:65-76
Fremont, Rachel; Tewari, Ambika; Angueyra, Chantal et al. (2017) A role for cerebellum in the hereditary dystonia DYT1. Elife 6:
Isaksen, Toke Jost; Kros, Lieke; Vedovato, Natascia et al. (2017) Hypothermia-induced dystonia and abnormal cerebellar activity in a mouse model with a single disease-mutation in the sodium-potassium pump. PLoS Genet 13:e1006763
Tewari, Ambika; Fremont, Rachel; Khodakhah, Kamran (2017) It's not just the basal ganglia: Cerebellum as a target for dystonia therapeutics. Mov Disord 32:1537-1545
Person, Abigail L; Khodakhah, Kamran (2016) Recurrent Feedback Loops in Associative Learning. Neuron 89:427-30
Alviña, K; Tara, E; Khodakhah, K (2016) Developmental change in the contribution of voltage-gated Ca(2+) channels to the pacemaking of deep cerebellar nuclei neurons. Neuroscience 322:171-7
Fremont, Rachel; Tewari, Ambika; Khodakhah, Kamran (2015) Aberrant Purkinje cell activity is the cause of dystonia in a shRNA-based mouse model of Rapid Onset Dystonia-Parkinsonism. Neurobiol Dis 82:200-212

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