Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia.
Episodic ataxia type-2 (EA2) is caused by mutations in P/Q-type voltage-gated calcium channels that are expressed at high densities in cerebellar Purkinje cells. Because P/Q channels support neurotransmitter release at many synapses, it is believed that ataxia is caused by impaired synaptic transmission. Here we show that in ataxic P/Q channel mutant mice, the precision of Purkinje cell pacemaking is lost such that there is a significant degradation of the synaptic information encoded in their activity. The irregular pacemaking is caused by reduced activation of calcium-activated potassium (K(Ca)) channels and was reversed by pharmacologically increasing their activity with 1-ethyl-2-benzimidazolinone (EBIO). Moreover, chronic in vivo perfusion of EBIO into the cerebellum of ataxic mice significantly improved motor performance. Our data support the hypothesis that the precision of intrinsic pacemaking in Purkinje cells is essential for motor coordination and suggest that K(Ca) channels may constitute a potential therapeutic target in EA2.
Walter
Joy T
JT
Department of Neuroscience, Albert Einstein College of Medicine, 506 Kennedy Center, 1410 Pelham Parkway South, Bronx, New York 10461, USA.
Alviña
Karina
K
Womack
Mary D
MD
Chevez
Carolyn
C
Khodakhah
Kamran
K
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001683:Biological Clocks / Q000187:drug effects / Q000235:genetics*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020865:Calcium Channels, P-Type / Q000187:drug effects / Q000235:genetics*; D002524:Cerebellar Ataxia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D002525:Cerebellar Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics*; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics
D001562:Benzimidazoles; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020865:Calcium Channels, P-Type; D024681:Potassium Channels, Calcium-Activated; C102635:1-ethyl-2-benzimidazolinone