Targeting Glial mGluR5 in Schizophrenia

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DESCRIPTION (provided by applicant): Schizophrenia is a multifactorial disease for which several theories have been postulated. It has also been hypothesized that a viral infection during pregnancy may alter or trigger improper fetal brain development. Indeed, prenatal injection of lipopolysaccharide or Poly I:C leads, in part, to sensorimotor gating deficits and locomotor sensitization to psychostimulant in rodent models later in life. These are two characteristics of schizophrenic patients. Interestingly, recent studies have demonstrated that the glutamatergic metabotropic receptor type 5 (mGluR5) is associated with disrupted sensorimotor gating response and altered psychostimulant-induced locomotor activity. mGluR5 is located both on neurons and glia. Variation in its expression could reflect functional changes of neuronal activity or participate in the inflammatory response, and serve as a new therapeutic target site. Aim 1. Investigation of the mGluR5 and inflammatory response in the poly I:C immune challenge animal model of schizophrenia. We hypothesize that the effects of Poly I:C will propagate a microglial activation and release of inflammatory mediators further aggravating the neuropathological conditions created by the toxin. Pregnant females mice at gestational day 9 will be injected with a dose of Poly I:C or saline. MicroPET imaging studies of inflammatory response using [11C]PK11195 and modulation of mGluR5 expression using [18F]FPEB, combined by behavioral studies, will be done at two time points (p35 (pre- puberty) and p80 (adulthood)) to relate the time course of inflammation to motor dysfunction and the extent of inflammatory response/modulation of mGluR5 function. Imaging will also be performed on pregnant females to assess these responses in the treated mothers and developing pups. End-point imaging studies will be correlated with post mortem analyses. Aim2. Investigation of the effect of mGluR5 agonist and antagonist on schizophrenia-like symptoms induced by poly I:C immune challenge. We propose that the pharmacological blockade of the inflammatory response will protect against inflammatory-induced neurotoxicity effects of Poly I:C. We propose to block this response with specific mGluR5 antagonist (2-methyl-6-(phenylethynyl)pyridine, MPEP) or positive allosteric modulator (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide, CDPPB). Experimental procedures are identical to aim 1. Data sets of both aims will be statistically analyzed to reveal the effect of either drugs or the extent and magnitude of inflammation as a component of schizophrenia-like pathology. Significance: The studies proposed will shed light on the pathogenesis of schizophrenia-like symptoms in immune-challenge animal models, and will allow testing treatment possibilities in the neurodevelopmental concept of the disease, challenging the current concept and treatment approaches of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a chronic and disabling disorder that affects more than 2 percent of population worldwide and the World Health Organization has thus identified this mental disease as one of the ten most debilitating diseases affecting human beings. Schizophrenia is a complex illness and there are several theories of its cause, including environmental factors and inflammation. In this project, we will investigate if metabotropic glutamate receptor function shows inflammation dependent modulation, which contributes to the development of schizophrenia and which would serve as a new therapeutic target site.