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.

Figure 1. Microcircuitry of the cerebellar cortex

The Purkinje neurons (PNs) provide the output from the cerebellar cortex modified by extrinsic excitatory synaptic inputs from mossy fibres (via granule cells, GCs) and climbing fibres (CFs). Synaptic activity can be directly modified by postsynaptic mGluR1‐dependent mechanisms to weaken the excitatory parallel fibre (PF) synapse (LTD). PN firing output is also further indirectly modified by PF activation of interneurons (basket cells, stellate cells) and Bergmann glia (BG). Golgi and unipolar brush cell activity influences GCs, so indirectly influencing PF input to PNs. The schematic diagram summarises Type 1 mGluR expression amongst the cells in the microcircuit, suggesting that there are a variety of opportunities for Type 1 mGluR pharmacological modulation in the circuit to directly or indirectly modify PN output. Note that mature PNs express the highest level of mGluR1 and do not express mGluR5. ML, molecular layer; GCL, granule cell layer; BG, Bergmann glia.

Figure 2. Type 1 mGluR signalling at healthy and ataxic cerebellar PF synapses

A summary of Type 1 mGluR signalling interactions at healthy (A) and ataxic (B) cerebellar PF synapses. Note the loss of key elements between A and B in a variety of clinically relevant ataxic mouse models and as a consequence of human mutations that cause ataxia. Spiral represents diverse downstream signalling pathways involving PKC and tyrosine‐dependent kinases and phosphatases where activity culminates in the removal of AMPA‐R from the postsynaptic membrane in LTD. It is not known if defects in these components occur in ataxias. Increased line thicknesses in B versus A indicates increased efficiency of coupling between mGluR5 and InsP ₃ mobilisation (compared with mGluR1) or increased Na⁺, Ca²⁺ or K⁺ ion fluxes.