Review
Metabotropic glutamate receptor 5 in the pathology and treatment of schizophrenia

https://doi.org/10.1016/j.neubiorev.2012.12.005Get rights and content

Abstract

Metabotropic glutamate receptor 5 (mGluR5) potentiates the NMDA receptor (NMDAR) in brain regions implicated in schizophrenia, making it a viable therapeutic target for the treatment of this disorder. mGluR5 positive allosteric modulators may represent a valuable novel strategy for schizophrenia treatment, given the favourable profile of effects in preclinical paradigms. However it remains unclear whether mGluR5 also plays a causal or epiphenomenal role in NMDAR dysfunction in schizophrenia. Animal and cellular data suggest involvement of mGluR5, whilst post-mortem human studies remain inconclusive. This review will explore the molecular, animal and human data to support and refute the involvement of mGluR5 in the pathology of schizophrenia. Furthermore, this review will discuss the potential of mGluR5 modulators in the therapy of schizophrenia as well as aspects of mGluR5 that require further characterisation.

Highlights

mGluR5 is of interest as a novel therapeutic target for schizophrenia. ► mGluR5 potentiates the NMDAR in brain regions implicated in schizophrenia. ► We review data that supports and refutes the involvement of mGluR5 in schizophrenia. ► We discuss the potential of mGluR5 modulators in the therapy of schizophrenia.

Introduction

Schizophrenia is a neuropsychiatric disorder distinguished by a set of symptoms that typically emerge in early adulthood. Schizophrenia is characterised by hallucinations and delusions (positive symptoms), deficits in learning and memory (cognitive symptoms), depression and social isolation (negative symptoms), among many more (Lewis and Lieberman, 2000). Although the exact cause of schizophrenia is undetermined, studies suggest the disease is neurodevelopmental (for review see Arnold et al., 2004, Marenco and Weinberger, 2000, McGrath et al., 2003), with both genetic and environmental factors triggering a ‘domino effect’ by which cellular and neurotransmitter systems within the brain are compromised (Lang et al., 2007).

An imbalance in dopaminergic neurotransmission has been well documented in schizophrenia (Toda and Abi-Dargham, 2007). Accumulated evidence includes the ability of dopamine-reuptake inhibitors to induce hallucinations and delusions homologous to the positive symptoms of schizophrenia (Matthysse, 1974), in addition to the capability of dopamine D2 receptor antagonists to successfully ameliorate some psychotic symptoms such as hallucinations and delusions (Andersson et al., 1998). However, dysfunction of the dopaminergic system does not account for the more discreet and debilitating symptoms seen in the disease, which have been attributed to disruptions in glutamatergic circuitry (Tsai and Coyle, 2002).

Glutamate has been linked to a myriad of processes surrounding cognition, memory and perception (Robbins and Murphy, 2006). Converging lines of evidence suggest dysfunction of the glutamatergic receptors is key to the aetiology of schizophrenia (Steele et al., 2012). Glutamate is an excitatory neurotransmitter present at the majority of synapses in the brain (Tsai and Coyle, 2002), and it is vital to neurodevelopment as well as synapse organisation and sensorimotor gating in adults (Arnold et al., 2004). Glutamate exerts effects through ionotropic and metabotropic receptors. Ionotropic glutamate receptors, which include N-methyl-d-aspartate receptors (NMDAR), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) and kainate receptors (Goff and Wine, 1997), are ligand-gated ion channels. Metabotropic glutamate receptors (mGluR) are G-protein-coupled receptors. Eight mGluRs (mGluR1-8) have been discovered and cloned thus far, and are grouped into three categories: Group 1 (mGluR1 and 5), Group 2 (mGluR2 and 3) and Group 3 (mGluR4, 6, 7 and 8) according to sequence homology, pharmacological properties and downstream activations (Niswender and Conn, 2010).

The glutamatergic hypothesis is a powerful explanatory model of schizophrenia. Of the proposed glutamatergic models, the NMDAR hypofunction model posits that dysregulation of glutamate is caused by reduced NMDAR function on GABAergic neurons in subcortical regions, leading to disinhibition of cortical glutamatergic efferents and a hyperglutamatergic state (Marek et al., 2010). This results in functional deficits in GABAergic interneurons, particularly parvalbumin-containing interneurons (Homayoun and Moghaddam, 2007, Nakazawa et al., 2012). This hypothesis is supported by the action of NMDAR antagonists, which are recognised precipitators of positive, negative and cognitive schizophrenia-like symptoms in humans and animals (Chartoff et al., 2005, Olney et al., 1999). These drugs also exacerbate symptoms of schizophrenia subjects (Javitt and Zukin, 1991), and adjunct treatment of schizophrenia subjects with glycine, a co-activator of NMDAR, improves aspects of schizophrenia symptomatology in some patients (Tsai and Coyle, 2002). This highlights dysfunction of glutamatergic signalling in schizophrenia.

Section snippets

Metabotropic glutamate receptor 5

Although the NMDAR is widely implicated in glutamatergic dysfunction associated with schizophrenia, it is unlikely that it is the solitary aetiological factor. Still, evidence suggests that many schizophrenia risk factors converge on the NMDAR rendering it of primary concern (Kantrowitz and Javitt, 2010). As excitatory glutamatergic neurotransmission is also modulated by mGluRs, it is possible that dysfunction within this aspect of glutamatergic circuitry may exist. In particular, Groups 1 and

The effect of current antipsychotic drugs on mGluR5

Antipsychotic drugs (APDs) are currently the primary form of treatment for schizophrenia patients. Whilst both first, second and third generation APDs competitively antagonise dopamine D2 receptors, second and third generation antipsychotics have a much more complex mode of action with various affinities for dopaminergic, serotonergic, muscarinic, adrenergic and histamatergic receptors (Coward, 1992, Seeman, 2002). Despite being widely efficacious for positive schizophrenia symptoms, APDs

mGluR5 as a therapeutic target for schizophrenia

As the NMDAR cannot be directly agonised as a therapy for schizophrenia due to the risk of excitotoxicity, indirect modulation of NMDAR through mGluR5 shows promise as mGluR5 is primarily distributed in brain regions relevant to schizophrenia. Consistent with mGluR5 antagonist effects discussed earlier, mGluR5 agonists have been shown to ameliorate cognitive impairments induced by NMDAR antagonists (Lecourtier et al., 2007, Stefani and Moghaddam, 2010, Vales et al., 2010). Additionally, Kinney

Future directions and final remarks

Although the involvement of mGluR5 in the pathological process of schizophrenia is uncertain, a growing body of evidence supports its ability to modulate the neurochemical dysfunction attributable to the disorder. Indeed, a lack of change of this receptor in schizophrenia is beneficial from a pharmacotherapy aspect, as its ability to modulate the NMDAR is potentially unhindered. Promising new data indicates that mGluR5 PAMs may be a valuable alternative or additional approach to treating

Acknowledgements

The authors gratefully acknowledge and extend thanks to the anonymous reviewers and the Centre for Translational Neurosciences Schizophrenia Research Group (UOW), for their invaluable comments, which have significantly contributed to the quality of the final manuscript.

This work was supported by the Schizophrenia Research Institute, utilising infrastructure funding from NSW Health.

References (147)

  • T.M. Du Bois et al.

    Early brain development disruption from NMDA receptor hypofunction: relevance to schizophrenia

    Brain Research Reviews

    (2007)
  • S.W. Fowler et al.

    Functional interaction of mGlu5 and NMDA receptors in aversive learning in rats

    Neurobiology of Learning and Memory

    (2011)
  • A. Francesconi et al.

    Role of the second and third intracellular loops of metabotropic glutamate receptors in mediating dual signal transduction activation

    Journal of Biological Chemistry

    (1998)
  • K. Fuxe et al.

    Receptor-receptor interactions within receptor mosaics: impact on neuropsychopharmacology

    Brain Research Reviews

    (2008)
  • F. Gastambide et al.

    The mGlu5 positive allosteric modulator LSN2463359 differentially modulates motor, instrumental and cognitive effects of NMDA receptor antagonists in the rat

    Neuropsychopharmacology

    (2013)
  • A.E. Geddes et al.

    Reciprocal signalling between NR2 subunits of the NMDA receptor and Neuregulin1 and their role in schizophrenia

    Progress in Neuro-Psychopharmacology and Biological Psychiatry

    (2011)
  • G. Gilmour et al.

    In vitro characterisation of the novel positive allosteric modulators of the mGlu 5 receptor, LSN2463359 and LSN2814617, and their effects on sleep architecture and operant responding in the rat

    Neuropharmacology

    (2013)
  • D.C. Goff et al.

    Glutamate in schizophrenia: clinical and research implications

    Schizophrenia Research

    (1997)
  • C.K. Gürkan et al.

    Targeted treatments in autism and fragile X syndrome

    Research in Autism Spectrum Disorders

    (2012)
  • S. Henry et al.

    The mGluR5 antagonist MPEP, but not the mGluR2/3 agonist LY314582, augments PCP effects on prepulse inhibition and locomotor activity

    Neuropharmacology

    (2002)
  • U. Heresco-Levy

    Glutamatergic neurotransmission modulation and the mechanisms of antipsychotic atypicality

    Progress in Neuro-Psychopharmacology and Biological Psychiatry

    (2003)
  • Y.Q. Huang et al.

    CAKβ/Pyk2 kinase is a signaling link for induction of long-term potentiation in CA1 hippocampus

    Neuron

    (2001)
  • F. Iasevoli et al.

    Ketamine-related expression of glutamatergic postsynaptic density genes: possible implications in psychosis

    Neuroscience Letters

    (2007)
  • F. Iasevoli et al.

    Haloperidol induces higher Homer1a expression than risperidone, olanzapine and sulpiride in striatal sub-regions

    Psychiatry Research

    (2010)
  • D. Inta et al.

    The mGlu5 receptor antagonist MPEP activates specific stress-related brain regions and lacks neurotoxic effects of the NMDA receptor antagonist MK-801: significance for the use as anxiolytic/antidepressant drug

    Neuropharmacology

    (2012)
  • J.T. Kantrowitz et al.

    N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia?

    Brain Research Bulletin

    (2010)
  • L. Lecourtier et al.

    Positive allosteric modulation of metabotropic glutamate 5 (mGlu5) receptors reverses N-methyl-d-aspartate antagonist-induced alteration of neuronal firing in prefrontal cortex

    Biological Psychiatry

    (2007)
  • D.A. Lewis et al.

    Catching up on schizophrenia: natural history and neurobiology

    Neuron

    (2000)
  • F. Liu et al.

    The effect of mGlu5 receptor positive allosteric modulators on signaling molecules in brain slices

    European Journal of Pharmacology

    (2006)
  • P. Malherbe et al.

    Identification and characterization of a novel splice variant of the metabotropic glutamate receptor 5 gene in human hippocampus and cerebellum

    Molecular Brain Research

    (2002)
  • J.A. Matta et al.

    mGluR5 and NMDA receptors drive the experience-and activity-dependent NMDA receptor NR2B to NR2A subunit switch

    Neuron

    (2011)
  • S. Matthysse

    Dopamine and the pharmacology of schizophrenia: the state of the evidence

    Journal of Psychiatric Research

    (1974)
  • D. Melchiorri et al.

    Metabotropic glutamate receptors in stem/progenitor cells

    Neuropharmacology

    (2007)
  • K. Nakazawa et al.

    GABAergic interneuron origin in schizophrenia pathophysiology

    Neuropharmacology

    (2012)
  • T. Ohnuma et al.

    Expression of the human excitatory amino acid transporter 2 and metabotropic glutamate receptors 3 and 5 in the prefrontal cortex from normal individuals and patients with schizophrenia

    Molecular Brain Research

    (1998)
  • T. Ohnuma et al.

    Gene expression of metabotropic glutamate receptor 5 and excitatory amino acid transporter 2 in the schizophrenic hippocampus

    Molecular Brain Research

    (2000)
  • J.W. Olney et al.

    NMDA receptor hypofunction model of schizophrenia

    Journal of Psychiatric Research

    (1999)
  • A. Pałucha et al.

    Potential antidepressant-like effect of MTEP, a potent and highly selective mGluR5 antagonist

    Pharmacology Biochemistry and Behavior

    (2005)
  • S. Parmentier-Batteur et al.

    Differential effects of the mGluR5 positive allosteric modulator CDPPB in the cortex and striatum following repeated administration

    Neuropharmacology

    (2012)
  • L.F. Agnati et al.

    An integrated view on the role of receptor mosaics at perisynaptic level: focus on adenosine A2A, dopamine D2, cannabinoid CB1, and metabotropic glutamate mGlu5 receptors

    Journal of Receptor and Signal Transduction Research

    (2010)
  • S.E. Arnold et al.

    Neurodevelopment, neuroplasticity, and new genes for schizophrenia

    Progress in Brain Research

    (2004)
  • S. Attucci et al.

    Activation of type 5 metabotropic glutamate receptors enhances NMDA responses in mice cortical wedges

    British Journal of Pharmacology

    (2001)
  • H. Awad et al.

    Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus

    Journal of Neuroscience

    (2000)
  • J.E. Ayala et al.

    mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning

    Neuropsychopharmacology

    (2009)
  • V.P. Bakshi et al.

    Antagonism of phencyclidine-induced deficits in prepulse inhibition by the putative atypical antipsychotic olanzapine

    Psychopharmacology

    (1995)
  • V.P. Bakshi et al.

    Disruption of prepulse inhibition and increases in locomotor activity by competitive N-methyl-d-aspartate receptor antagonists in rats

    Journal of Pharmacology and Experimental Therapeutics

    (1999)
  • R. Balázs et al.

    Metabotropic glutamate receptor mGluR5 in astrocytes: pharmacology, properties and agonist regulation

    Journal of Neurochemistry

    (1997)
  • P. Benquet et al.

    Two distinct signaling pathways upregulate NMDA receptor responses via two distinct metabotropic glutamate receptor subtypes

    Journal of Neuroscience

    (2002)
  • J. Brodkin et al.

    Reduced stress-induced hyperthermia in mGluR5 knockout mice

    European Journal of Neuroscience

    (2002)
  • C.S. Busse et al.

    The behavioral profile of the potent and selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl] pyridine (MTEP) in rodent models of anxiety

    Neuropharmacology

    (2004)
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