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

Tabita Kreko-Pierce,Donald G. Harbidge,James D. Stockand,Nina Boiko,Daniel C. Marcus,Jason R. Pugh

doi:10.1038/s41598-020-58901-y

Tabita Kreko-Pierce, Donald G. Harbidge + Show 4 more

Open Access

https://doi.org/10.1038/s41598-020-58901-y

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Abstract

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.

Highlights

The cerebellum plays a key role in the control of balance, and motor coordination and precision
The primary conclusions supported by this work are that acid-sensing ion channels (Asics)[5] serves a key function in type II Unipolar brush cells (UBCs), influencing intrinsic excitability and the firing of spontaneous action potentials, as well as, glutamate-sensitive burst firing; and that deletion of Asic[5] causes discoordination
There likely is a cause and effect relation between these two observations such that type II UBCs serve a key role in the vestibulocerebellum, and their dysfunction here due to abnormal Asic[5] activity causes a mild form of ataxia

Summary

Introduction

The cerebellum plays a key role in the control of balance, and motor coordination and precision. Type I UBCs typically fire spontaneously at relatively high frequencies and glutamate provokes an inhibitory response This inhibitory response in type I UBCs results from little AMPAR-mediated current combined with robust outward. Through analogy to the retina, such observations have refined understanding of UBC function: In response to MF glutamatergic transmission, type II UBCs may function as ON cells that upregulate spiking following a brief phase delay; and, type I UBCs may function as OFF cells with downregulated firing in response to glutamate resulting in a phase inversion Together these two types of UBCs allow distinct parallel processing of their inputs to their target GCs resulting in diverse phase coding capable of enhancing adaptive control of behavior by facilitating appropriate output in a broad temporal window[5,6,9,10,11]

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