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

ELife
Pratap MeeraThomas S Otis

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 [Ca(2+)] at normal resting levels while in wildtype PNs mGluR1 EPSCs are enhanced by elevated [Ca(2+)]. 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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Citations

Jan 2, 2020·International Journal of Molecular Sciences·Francesca PrestoriEgidio D'Angelo
Aug 23, 2019·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Polina A Egorova, Ilya B Bezprozvanny
Apr 21, 2020·Human Molecular Genetics·Daniel R ScolesStefan M Pulst
Mar 22, 2018·Annals of Clinical and Translational Neurology·David D BushartVikram G Shakkottai
Dec 12, 2018·Proceedings of the National Academy of Sciences of the United States of America·Alexander S BrownAnthony E Oro
May 16, 2018·Frontiers in Synaptic Neuroscience·Eriola HoxhaFilippo Tempia
May 24, 2019·Neurology. Genetics·Daniel R ScolesStefan M Pulst
Jul 10, 2019·Movement Disorders : Official Journal of the Movement Disorder Society·Daniel R Scoles, Stefan M Pulst
Apr 23, 2020·Frontiers in Neuroscience·Polina A EgorovaIlya B Bezprozvanny
Apr 18, 2020·Frontiers in Neuroscience·Francesca BindaSmita Saxena
Aug 9, 2020·Frontiers in Neuroscience·Katherine J RobinsonAngela S Laird
Mar 22, 2021·Annals of Neurology·Sharan PaulStefan M Pulst

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