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Altered expression of schizophrenia-related genes in mice lacking mGlu5 receptors

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Abstract

The evidence underlying the so-called glutamatergic hypothesis ranges from NMDA receptor hypofunction to an imbalance between excitatory and inhibitory circuits in specific brain structures. Among all glutamatergic system components, metabotropic receptors play a main role in regulating neuronal excitability and synaptic plasticity. Here, we investigated, using qRT-PCR and western blot, consequences in the hippocampus and prefrontal/frontal cortex (PFC/FC) of mice with a genetic deletion of the metabotropic glutamate receptor 5 (mGlu5), addressing key components of the GABAergic and glutamatergic systems. We found that mGlu5 knockout (KO) mice showed a significant reduction of reelin, GAD65, GAD67 and parvalbumin mRNA levels, which is specific for the PFC/FC, and that is paralleled by a significant reduction of protein levels in male KO mice. We next analyzed the main NMDA and AMPA receptor subunits, namely GluN1, GluN2A, GluN2B and GluA1, and we found that mGlu5 deletion determined a significant reduction of their mRNA levels, also within the hippocampus, with differences between the two genders. Our data suggest that neurochemical abnormalities impinging the glutamatergic and GABAergic systems may be responsible for the behavioral phenotype associated with mGlu5 KO animals and point to the close interaction of these molecular players for the development of neuropsychiatric disorders such as schizophrenia. These data could contribute to a better understanding of the involvement of mGlu5 alterations in the molecular imbalance between excitation and inhibition underlying the emergence of a schizophrenic-like phenotype and to understand the potential of mGlu5 modulators in reversing the deficits characterizing the schizophrenic pathology.

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Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft (IN-168/3-1) to D.I. and P.G. and by Ministry of Health, Italy—Ricerca Sanitaria Finalizzata, GET UP Project Code H61J08000200001 to P.B., M.R. and M.A.R.

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Authors and Affiliations

  1. Department of Pharmacological and Biomolecular Sciences, Center of Neuropharmacology, Università degli Studi di Milano, Milan, Italy

    Alessia Luoni & Marco A. Riva

  2. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, University of Heidelberg, J 5, 68159, Mannheim, Germany

    Peter Gass & Dragos Inta

  3. Department of Psychiatry (UPK), University of Basel, Wilhelm Klein-Str. 27, 4012, Basel, Switzerland

    Dragos Inta

  4. Department of Neurosciences and Mental Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

    Paolo Brambilla

  5. Section of Psychiatry, Department of Neurological, Biomedical and Movement Sciences, University of Verona, Verona, Italy

    Mirella Ruggeri

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  1. Alessia Luoni
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  3. Paolo Brambilla
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Correspondence to Dragos Inta.

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Luoni, A., Gass, P., Brambilla, P. et al. Altered expression of schizophrenia-related genes in mice lacking mGlu5 receptors. Eur Arch Psychiatry Clin Neurosci 268, 77–87 (2018). https://doi.org/10.1007/s00406-016-0728-z

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