Cerebellar Ataxia Caused by Type II Unipolar Brush Cell Dysfunction in the Asic5 Knockout Mouse.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Action Potentials*; Acid Sensing Ion Channels/*genetics ; Cerebellar Ataxia/*metabolism ; Neurons/*metabolism; Animals ; Cerebellar Ataxia/genetics ; Cerebellar Ataxia/pathology ; Glutamic Acid/metabolism ; Male ; Mice ; Neurons/physiology ; Potassium/metabolism

Unipolar brush cells (UBCs) are excitatory granular layer interneurons in the vestibulocerebellum. Here we assessed motor coordination and balance to investigate if deletion of acid-sensing ion channel 5 (Asic5), which is richly expressed in type II UBCs, is sufficient to cause ataxia. The possible cellular mechanism underpinning ataxia in this global Asic5 knockout model was elaborated using brain slice electrophysiology. Asic5 deletion impaired motor performance and decreased intrinsic UBC excitability, reducing spontaneous action potential firing by slowing maximum depolarization rate. Reduced intrinsic excitability in UBCs was partially compensated by suppression of the magnitude and duration of delayed hyperpolarizing K ⁺ currents triggered by glutamate. Glutamate typically stimulates burst firing subsequent to this hyperpolarization in normal type II UBCs. Burst firing frequency was elevated in knockout type II UBCs because it was initiated from a more depolarized potential compared to normal cells. Findings indicate that Asic5 is important for type II UBC activity and that loss of Asic5 contributes to impaired movement, likely, at least in part, due to altered temporal processing of vestibular input.

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R01 DK117909 United States DK NIDDK NIH HHS; R01 DK087460 United States DK NIDDK NIH HHS; T32 HL007446 United States HL NHLBI NIH HHS; R01 DK113816 United States DK NIDDK NIH HHS; R01 NS092809 United States NS NINDS NIH HHS

0 (Acid Sensing Ion Channels)
0 (Asic5 protein, mouse)
3KX376GY7L (Glutamic Acid)
RWP5GA015D (Potassium)

Date Created: 20200209 Date Completed: 20201110 Latest Revision: 20210206

20250114

PMC7005805

10.1038/s41598-020-58901-y

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