Abstract

BackgroundPharmacological modulation of metabotropic glutamate receptor 5 (mGluR5) is of marked interest as a novel therapeutic mechanism to treat schizophrenia and major depression. However, the status of mGluR5 in the pathophysiology of these disorders remains unknown.DiscussionThe majority of studies in the schizophrenia post-mortem brain indicate that total mGluR5 expression is unaltered. However, close examination of the literature suggests that these findings are superficial, and in actuality, a number of critical factors have not yet been considered; alterations may be highly dependent on brain region, neuronal population or molecular organisation in specific cellular compartments. A number of genetic knockout studies (mGluR5, Norbin, Homer1 etc.) continue to lend support to a role of mGluR5 in the pathology of schizophrenia, providing impetus to explore the regulation of mGluR5 beyond total mGluR5 protein and mRNA levels. With regards to major depression, preliminary evidence to date shows a reduction in total mGluR5 protein and mRNA levels; however, as in schizophrenia, there are no studies examining mGluR5 function or regulation in the pathological state. A comprehensive understanding of mGluR5 regulation in major depression, particularly in comparison to schizophrenia, is crucial as this has extensive implications for mGluR5 targeting novel therapeutics, especially considering that opposing modulation of mGluR5 is of therapeutic interest for these two disorders.SummaryDespite the complexities, examinations of post-mortem human brain provide valuable insights into the pathologies of these inherently human disorders. It is important, especially with regards to the identification of novel therapeutic drug targets, to have an in depth understanding of the pathophysiologies of these disorders. We posit that brain region- and cell type-specific alterations exist in mGluR5 in schizophrenia and depression, with evidence pointing towards altered regulation of this receptor in psychiatric pathology. We consider the implications of these alterations, as well as the distinction between schizophrenia and depression, in the context of novel mGluR5 based therapeutics.

Highlights

  • Pharmacological modulation of metabotropic glutamate receptor 5 is of marked interest as a novel therapeutic mechanism to treat schizophrenia and major depression

  • We posit that brain region- and cell type-specific alterations exist in metabotropic glutamate receptor 5 (mGluR5) in schizophrenia and depression, with evidence pointing towards altered regulation of this receptor in psychiatric pathology

  • We consider the implications of these alterations, as well as the distinction between schizophrenia and depression, in the context of novel mGluR5 based therapeutics

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Summary

Discussion

Neuropathological findings and considerations Protein studies Post-mortem analyses of human brain tissue from psychiatric patients provide valuable insight into the potential pathophysiology of these disorders. Compared to mGluR5a and b, the mGluR5d isoform has increased sensitivity to desensitisation and has a shorter intracellular c-terminus by a significant 267 amino acids [36]; mGluR5d has less interaction with scaffolding molecules that modulate the mGluR5/NMDAR complex (e.g. Homer), and other endogenous molecules that ensure its trafficking and cell surface localisation This is important to consider, especially in the context of schizophrenia where the majority of studies indicate no change in overall mGluR5 levels; there may in reality be altered regulation, trafficking or recycling of mGluR5 or altered receptor-receptor interactions.

Findings
Background

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