Are Type 1 metabotropic glutamate receptors a viable therapeutic target for the treatment of cerebellar ataxia?

Abstract

The cerebellum is a key brain structure for accurate coordination of sensory and motor function. Compared with other brain regions, the cerebellum expresses a particularly high level of Type 1 metabotropic glutamate receptors (mGluR1). In this review we aim to explore the significance of these receptors for cerebellar synapse function and their potential for treating cerebellar ataxia, a poorly treated degenerative motor disorder that is often hereditary. We find a significant and historical literature showing pivotal mechanisms linking mGluR1 activity with healthy cerebellar synaptic function and motor coordination. This is best illustrated by the impaired motor behaviour in mGluR1 knockout mice that bears strong resemblance to human ataxias. More recent literature also indicates that an imbalance of mGluR1 signalling is as critical as its removal. Too much, as well as too little, mGluR1 activity contributes to ataxia in several clinically relevant mouse models, and perhaps also in humans. Given the availability and ongoing refinement of selective pharmacological tools to either reduce (negative allosteric modulation) or boost (positive allosteric modulation) mGluR1 activity, our findings suggest that pharmacological manipulation of these receptors should be explored as an exciting new approach for the treatment of a variety of human cerebellar ataxias.