A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2

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Abstract

Metabotropic glutamate receptor 1 (mGluR1) function in Purkinje neurons (PNs) is essential for cerebellar development and for motor learning and altered mGluR1 signaling causes ataxia. Downstream of mGluR1, dysregulation of calcium homeostasis has been hypothesized as a key pathological event in genetic forms of ataxia but the underlying mechanisms remain unclear. We find in a spinocerebellar ataxia type 2 (SCA2) mouse model that calcium homeostasis in PNs is disturbed across a broad range of physiological conditions. At parallel fiber synapses, mGluR1-mediated excitatory postsynaptic currents (EPSCs) and associated calcium transients are increased and prolonged in SCA2 PNs. In SCA2 PNs, enhanced mGluR1 function is prevented by buffering [Ca²⁺] at normal resting levels while in wildtype PNs mGluR1 EPSCs are enhanced by elevated [Ca²⁺]. These findings demonstrate a deleterious positive feedback loop involving elevated intracellular calcium and enhanced mGluR1 function, a mechanism likely to contribute to PN dysfunction and loss in SCA2.

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Pratap Meera

Department of Neurobiology, University of California, Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Stefan Pulst

Department of Neurology, University of Utah, Salt Lake City, United States

Competing interests
The authors declare that no competing interests exist.
Thomas Otis

Neuroscience, Ophthalmology, & Rare Diseases (NORD), Roche Pharmaceutical Research and Early Development (pRED), Basel, Switzerland

For correspondence
thomas_stephen.otis@roche.com

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0383-8928

Funding

NIH Office of the Director (NS 033123)

Thomas Otis

NIH Office of the Director (NS 090930)

Thomas Otis

NIH Office of the Director (NS 033123)

Stefan Pulst

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#08-133) of the University of California Los Angeles. The protocol was approved by the Chancellor's Animal Research Committee (Permit Number: 1998-139).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.