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

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] at normal resting levels while in wildtype PNs mGluR1 EPSCs are enhanced by elevated [Ca]. 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.