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

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.

Keywords: animal models of schizophrenia; clinical trials; drug development; metabotropic glutamate receptors; negative allosteric modulators; positive allosteric modulators; schizophrenia.

Figure 1

The signaling pathways downstream mGluRs. Group I mGluR is coupled to G_q protein, which stimulates phospholipase C (PLC) and the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP₂). PIP₂ hydrolysis gives rise to inositol (1,4,5)-triphosphate (IP₃) and diacylglycerol (DAG). The IP₃ diffuses freely to the endoplasmic reticulum and activates the IP₃ receptors to release Ca²⁺ to the cytosol. By contrast, mGluRs of group II and III classically couple to G_i/o proteins and inhibit adenylyl cyclase, thus affecting downstream signaling pathways via liberation of Gβγ.