Metabotropic glutamate receptor 3 as a potential therapeutic target for psychiatric and neurological disorders

Abstract

Glutamate is a major excitatory neurotransmitter in the central nervous system (CNS) and abnormalities in the glutamatergic system underlie various CNS disorders. As metabotropic glutamate receptor 3 (mGlu₃ receptor) regulates glutamatergic transmission in various brain areas, emerging literature suggests that targeting mGlu₃ receptors can be a novel approach to the treatment of psychiatric and neurological disorders. For example, mGlu₃ receptor negative allosteric modulators (NAMs) induce rapid antidepressant-like effects in both acute and chronic stress models. Activation of mGlu₃ receptors can enhance cognition in the rodents modeling schizophrenia-like pathophysiology. The mGlu₃ receptors expressed in the astrocytes induce neuroprotective effects. Although polymorphisms in GRM3 have been shown to be associated with addiction, there is not significant evidence about the efficacy of mGlu₃ receptor ligands in rodent models of addiction. Collectively, drugs targeting mGlu₃ receptors may provide an alternative approach to fill the unmet clinical need for safer and more efficacious therapeutics for CNS disorders.

Keywords: Antidepressants; Cognition; Depression; Glutamate; Neurodevelopmental disorders; Schizophrenia; Substance use disorders; mGlu3; mGlu5.

Figure 1:

(A) Representative structure of an ionotropic glutamate (iGlu) receptor subunit. The iGluRs consist of one extracellular (EC) amino-terminal domain and one ligand binding domain (LBD). The LBD is connected to three transmembrane domains (TMDs). The transmembrane domain is in turn connected to intracellular (IC) C-terminal tail. In iGluRs, ligands bind to the orthosteric site in the LBD and the allosteric modulators bind to the ATD or LBD and channel blockers bind within the ion-channel forming TMD. (B) Representative structure of a metabotropic glutamate (mGlu) receptor subunit. The mGlu receptors have a larger EC domain known as Venus-flytrap domain (VFD) which is connected to seven transmembrane-spanning domains via cysteine rich domain (CRD). The transmembrane domain is in turn connected to intracellular C-terminal tail. The VFD binds glutamate and other orthosteric agonists, whereas the allosteric modulators bind in the TMD. These figures were created with BioRender.com.

Figure 2:

Schematic depicting mGlu₃ receptor-dependent functions in pyramidal neurons and astrocytes. Activation of mGlu₃ receptors in the postsynaptic neurons mobilizes endocannabinoids (2-arachindonylglycerol; 2-AG) via a mGlu₅ receptor-dependent signaling. Mobilization of 2-AG decreases the release of GABA from local interneurons leading to decreased inhibitory tone on pyramidal neurons and altered threshold for synaptic plasticity via N-methyl-D-aspartate (NMDA) receptors. Facilitating synaptic pathway through this mechanism enhances hippocampal-dependent cognition and can rescue cognitive deficits in rodents modeling schizophrenia-like pathophysiology. Activation of astrocytic mGlu₃ receptors can promote the release of brain derived neurotrophic factor (BDNF) that has neuroprotective effects. Activation of mGlu₃ receptor in the astrocytes also enhances the synthesis and release of anti-inflammatory cytokine transforming growth factor-β (TGF β) from astrocyte that protects neurons from excitotoxic insults. Astrocytic mGlu₃ receptor activation also enhances glial derived neurotropic factor (GDNF) levels indicating potential role of enhancing mGlu₃ receptor function in slowing neurodegeneration. AMPA- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA- γ-Aminobutyric acid; LTP- long-term potentiation; EAAT1- Excitatory amino acid transporter 1; EAAT2- Excitatory amino acid transporter 1. This figure was created with BioRender.com.