The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment—A Narrative Review

Waldemar Kryszkowski,Tomasz Boczek

doi:10.3390/jcm10071475

Abstract

Schizophrenia is a severe neuropsychiatric disease with an unknown etiology. The research into the neurobiology of this disease led to several models aimed at explaining the link between perturbations in brain function and the manifestation of psychotic symptoms. The glutamatergic hypothesis postulates that disrupted glutamate neurotransmission may mediate cognitive and psychosocial impairments by affecting the connections between the cortex and the thalamus. In this regard, the greatest attention has been given to ionotropic NMDA receptor hypofunction. However, converging data indicates metabotropic glutamate receptors as crucial for cognitive and psychomotor function. The distribution of these receptors in the brain regions related to schizophrenia and their regulatory role in glutamate release make them promising molecular targets for novel antipsychotics. This article reviews the progress in the research on the role of metabotropic glutamate receptors in schizophrenia etiopathology.

Highlights

Schizophrenia is a common debilitating disease affecting about 0.3–1% of the human population worldwide [1]
A strong line of evidence from the preclinical studies indicates that representatives of all three groups of Metabotropic Glutamate Receptors (mGluRs) should be considered when designing novel therapeutical strategies in schizophrenia treatment
The distribution of mGluR subtypes in brain regions traditionally linked with schizophrenia deficits, their modulatory action on other disease-associated receptors such as NMDA, AMPA or GABA(A) as well as the efficacy of their agonists or positive allosteric modulators (PAM) provide a strong foundation for considering mGluRs as potential targets for new generation antipsychotics

Summary

Introduction

Schizophrenia is a common debilitating disease affecting about 0.3–1% of the human population worldwide [1]. The symptoms of schizophrenia are usually classified into three main groups: positive (e.g., auditory and visual hallucinations, disorganized thought, delusions, odd behaviors), negative (e.g., social withdrawal, flattened affect) and cognitive (e.g., dysfunctions in working memory, attention, visual and verbal learning). Cognitive deficits are among the core symptoms present in almost 98% of patients with schizophrenia [2]. They usually manifest prior to the onset of psychosis and persist, but evolve during disease development. While most current antipsychotics act on dopaminergic and serotonergic systems, there is an urgent need to identify both new molecules and pharmacological targets with higher safety and efficiency toward core schizophrenia symptoms

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