Metabotropic glutamate receptor 5 binding and protein expression in schizophrenia and following antipsychotic drug treatment

Metabotropic glutamate receptor 5 (mGluR5) has been identified as a potential therapeutic target for schizophrenia, primarily due to its ability to indirectly modulate glutamatergic signalling through the NMDA receptor (NMDAR). Despite its potential, molecular studies characterising mGluR5 in schizophrenia are limited. We therefore aimed to determine if the mGluR5 binding site or protein levels were altered in schizophrenia or by current antipsychotics. Using in-situ radioligand binding and immunoblot, we measured [(3)H]MPEP binding to mGluR5 and mGluR5 protein density in the post-mortem dorsolateral prefrontal cortex (DLPFC; BA46) of 37 schizophrenia and 37 matched control subjects. Subsequently, we measured [(3)H]MPEP binding in rat brains following typical (haloperidol) or atypical (olanzapine) antipsychotic treatment (n = 6/group). Subjects with schizophrenia showed no significant alteration in mGluR5 binding density or mGluR5 protein levels. Furthermore, mGluR5 binding in the rat cortex, thalamus, hippocampus and striatum was unaltered by short-, medium- and long-term antipsychotic treatment. Our data suggests that there are no alterations in mGluR5 in schizophrenia subjects. The lack of alteration in mGluR5 binding and protein in schizophrenia is advantageous because its ability to modulate the NMDAR is potentially unhindered, thereby supporting the development of novel antipsychotic agents that work through the mGluR5/NMDAR complex.

[1]  P. Schofield,et al.  Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia , 2012, Molecular Psychiatry.

[2]  J. Pin,et al.  Interaction of Novel Positive Allosteric Modulators of Metabotropic Glutamate Receptor 5 with the Negative Allosteric Antagonist Site Is Required for Potentiation of Receptor Responses , 2007, Molecular Pharmacology.

[3]  L. Grégoire,et al.  mGluR5 metabotropic glutamate receptors and dyskinesias in MPTP monkeys , 2008, Neurobiology of Aging.

[4]  Gregor Hasler,et al.  Reduced metabotropic glutamate receptor 5 density in major depression determined by [(11)C]ABP688 PET and postmortem study. , 2011, The American journal of psychiatry.

[5]  P. Conn,et al.  Metabotropic Glutamate Subtype 5 Receptors Modulate Locomotor Activity and Sensorimotor Gating in Rodents , 2003, Journal of Pharmacology and Experimental Therapeutics.

[6]  P. McKenna,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. , 1998, Brain research. Molecular brain research.

[7]  M. Raiteri,et al.  Functional interactions between presynaptic NMDA receptors and metabotropic glutamate receptors co‐expressed on rat and human noradrenergic terminals , 2007, British journal of pharmacology.

[8]  Natalie Matosin,et al.  Metabotropic glutamate receptor 5 in the pathology and treatment of schizophrenia , 2013, Neuroscience & Biobehavioral Reviews.

[9]  M. Gerstein,et al.  Comparing protein abundance and mRNA expression levels on a genomic scale , 2003, Genome Biology.

[10]  K. Newell,et al.  Effects of antipsychotic medication on muscarinic M1 receptor mRNA expression in the rat brain , 2008, Journal of neuroscience research.

[11]  J. Benovic,et al.  Reduced expression of G protein-coupled receptor kinases in schizophrenia but not in schizoaffective disorder , 2011, Neurobiology of Disease.

[12]  B. Ellenbroek.  Psychopharmacological treatment of schizophrenia: What do we have, and what could we get? , 2012, Neuropharmacology.

[13]  J. Cohen,et al.  Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. , 2001, The American journal of psychiatry.

[14]  J. Massagué.  TGF-beta signal transduction. , 1998, Annual review of biochemistry.

[15]  P. Worley,et al.  Coupling of mGluR/Homer and PSD-95 Complexes by the Shank Family of Postsynaptic Density Proteins , 1999, Neuron.

[16]  G. Muscettola,et al.  Haloperidol induces higher Homer1a expression than risperidone, olanzapine and sulpiride in striatal sub-regions , 2010, Psychiatry Research.

[17]  G Bernardi,et al.  Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-D-aspartate responses in medium spiny striatal neurons , 2001, Neuroscience.

[18]  I. Mansuy,et al.  NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin , 2005, Neuropharmacology.

[19]  P. McKenna,et al.  Gene expression of metabotropic glutamate receptor 5 and excitatory amino acid transporter 2 in the schizophrenic hippocampus. , 2000, Brain research. Molecular brain research.

[20]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[21]  P. Conn,et al.  Metabotropic glutamate receptors as therapeutic targets for schizophrenia , 2012, Neuropharmacology.

[22]  B. Moghaddam,et al.  Bursting of prefrontal cortex neurons in awake rats is regulated by metabotropic glutamate 5 (mGlu5) receptors: rate-dependent influence and interaction with NMDA receptors. , 2006, Cerebral cortex.

[23]  D. Volk,et al.  Alterations in metabotropic glutamate receptor 1α and regulator of G protein signaling 4 in the prefrontal cortex in schizophrenia. , 2010, The American journal of psychiatry.

[24]  M. Webster,et al.  Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia. , 2010, The American journal of psychiatry.

[25]  G. Birk,et al.  The Selective mGlu5 Receptor Antagonist MTEP, Similar to NMDA Receptor Antagonists, Induces Social Isolation in Rats , 2007, Neuropsychopharmacology.

[26]  U. Gerber,et al.  Two Distinct Signaling Pathways Upregulate NMDA Receptor Responses via Two Distinct Metabotropic Glutamate Receptor Subtypes , 2002, The Journal of Neuroscience.

[27]  K. Fuxe,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 , 2010, Journal of receptor and signal transduction research.

[28]  P. Conn,et al.  Metabotropic glutamate receptors: physiology, pharmacology, and disease. , 2010, Annual review of pharmacology and toxicology.

[29]  Karen Faith Berman,et al.  Executive Function, Neural Circuitry, and Genetic Mechanisms in Schizophrenia , 2010, Neuropsychopharmacology.

[30]  Abraham Weizman,et al.  The possible involvement of metabotropic glutamate receptors in schizophrenia , 2008, European Neuropsychopharmacology.

[31]  M. Geyer,et al.  Assessment of a prepulse inhibition deficit in a mutant mouse lacking mGlu5 receptors , 2004, Molecular Psychiatry.

[32]  Xu-Feng Huang,et al.  Effects of olanzapine on muscarinic M3 receptor binding density in the brain relates to weight gain, plasma insulin and metabolic hormone levels , 2012, European Neuropsychopharmacology.

[33]  P. Dodd,et al.  Biochemical and molecular studies using human autopsy brain tissue , 2003, Journal of neurochemistry.

[34]  Younglim Lee,et al.  Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain? , 2010, Molecular Pharmacology.

[35]  C. Weickert,et al.  Increased Interstitial White Matter Neuron Density in the Dorsolateral Prefrontal Cortex of People with Schizophrenia , 2011, Biological Psychiatry.

[36]  Y. Smith,et al.  NMDA-induced phosphorylation and regulation of mGluR5 , 2002, Pharmacology Biochemistry and Behavior.

[37]  K. Davis,et al.  Metabotropic glutamate receptor protein expression in the prefrontal cortex and striatum in schizophrenia , 2005, Synapse.

[38]  D. Javitt,et al.  N-methyl-d-aspartate (NMDA) receptor dysfunction or dysregulation: The final common pathway on the road to schizophrenia? , 2010, Brain Research Bulletin.

[39]  B. Moghaddam,et al.  Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release , 2004, Neuropsychopharmacology.

[40]  Selection of Reference Gene Expression in a Schizophrenia Brain Cohort , 2010, The Australian and New Zealand journal of psychiatry.

[41]  E. Frank,et al.  Density of metabotropic glutamate receptors 2 and 3 (mGluR2/3) in the dorsolateral prefrontal cortex does not differ with schizophrenia diagnosis but decreases with age , 2011, Schizophrenia Research.

[42]  J. Kleinman,et al.  Comparative analysis of group II metabotropic glutamate receptor immunoreactivity in Brodmann's area 46 of the dorsolateral prefrontal cortex from patients with schizophrenia and normal subjects , 2002, Molecular Psychiatry.

[43]  B. Moghaddam,et al.  Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs , 2008, Proceedings of the National Academy of Sciences.

[44]  K. Davis,et al.  Metabotropic glutamate receptor mRNA expression in the schizophrenic thalamus , 2000, Biological Psychiatry.

[45]  P. Slater,et al.  Frontal Cortical and Left Temporal Glutamatergic Dysfunction in Schizophrenia , 1989, Journal of neurochemistry.

[46]  L. Crepaldi,et al.  Altered levels of glutamatergic receptors and Na+/K+ ATPase-α1 in the prefrontal cortex of subjects with schizophrenia , 2011, Schizophrenia Research.