ReviewMetabotropic glutamate receptor 5 in the pathology and treatment of schizophrenia
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.
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2020, Journal of Psychiatric ResearchCitation Excerpt :Interestingly, we did observe a moderate negative correlation between mGluR5 mRNA threshold cycle values in BA10 and lifetime antipsychotic drug dosage (LADD), suggesting that mGluR5 mRNA levels are moderately increased throughout the duration of chronic treatment. MGluR5 was first proposed to be involved in schizophrenia pathophysiology due to its functional colocalization with the NMDA receptor (Matosin and Newell, 2013). It is therefore possible that chronic antipsychotic treatment may be effective in part via regulation of mGluR5 and/or NMDA receptor expression.