Modulation of basal ganglia function by metabotropic glutamate receptors

Abstract

Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that play important roles in the modulation of neurotransmission in the central nervous system (CNS). The eight subtypes of mGluRs are differentially distributed throughout the CNS, where they act postsynaptically to modulate neuronal excitability and presynaptically to regulate neurotransmitter release. Until recently, a lack of subtype-selective pharmacological tools useful for determining the roles of each mGluR subtype has hindered efforts to elucidate the unique functions of individual mGluRs. The recent discovery of subtype-selective compounds that enhance or inhibit the activity of specific mGluRs has dramatically increased our understanding of mGluR-mediated modulation of CNS function and has led to the identification of mGluRs as targets for treating a variety of neurological and psychiatric disorders including Parkinson’s disease (PD) and schizophrenia. We have used both newly discovered and recently reported subtype-selective compounds to evaluate the roles of various mGluR subtypes in the regulation of the basal ganglia, which are a group of highly interconnected subcortical nuclei that are critical to the control of normal motor activity. Neurotransmission in the basal ganglia is pathologically altered in movement disorders such as PD, and drugs that can reverse aberrant increases in neurotransmission at various synapses are hypothesized to reduce motor symptoms. We have used a combination of behavioral and electrophysiological methods to evaluate the therapeutic potential of activation of mGluR4, mGluR8, and mGluR2 for the treatment of PD. Our results suggest that activation of all three of these mGluR subtypes could alleviate motor symptoms in PD. Interestingly, each subtype is likely to confer its beneficial effects through a distinct physiological mechanism. mGluR5 activation has been suggested as a novel therapeutic strategy for the treatment of schizophrenia, and compounds that enhance mGluR5 activation have behavioral effects in rodent models that are predictive of antipsychotic activity. We have evaluated the ability of various mGluR5 PAMs to modulate Akt and glycogen synthase kinase-3â signaling in the striatum, and found that mGluR5 PAMs might reverse hyperdopaminergia-mediated behaviors via activation of the Akt pathway. Taken together, these studies increase our understanding of the roles of individual mGluR subtypes in regulating basal ganglia function, and support the hypothesis that mGluRs represent important targets for treating a variety of CNS disorders that are not adequately managed using currently available medications.