title: Pharmacological activation of group-II metabotropic glutamate receptors corrects a schizophrenia-like phenotype induced by prenatal stress in mice.
abstract: Prenatal exposure to restraint stress causes long-lasting changes in neuroplasticity that likely reflect pathological modifications triggered by early-life stress. We found that the offspring of dams exposed to repeated episodes of restraint stress during pregnancy (here named 'prenatal restraint stress mice' or 'PRS mice') developed a schizophrenia-like phenotype, characterized by a decreased expression of brain-derived neurotrophic factor and glutamic acid decarboxylase 67, an increased expression of type-1 DNA methyl transferase (DNMT1) in the frontal cortex, and a deficit in social interaction, locomotor activity, and prepulse inhibition. PRS mice also showed a marked decrease in metabotropic glutamate 2 (mGlu2) and mGlu3 receptor mRNA and protein levels in the frontal cortex, which was manifested at birth and persisted in adult life. This decrease was associated with an increased binding of DNMT1 to CpG-rich regions of mGlu2 and mGlu3 receptor promoters and an increased binding of MeCP2 to the mGlu2 receptor promoter. Systemic treatment with the selective mGlu2/3 receptor agonist LY379268 (0.5 mg/kg, i.p., twice daily for 5 days), corrected all the biochemical and behavioral abnormalities shown in PRS mice. Our data show for the first time that PRS induces a schizophrenia-like phenotype in mice, and suggest that epigenetic changes in mGlu2 and mGlu3 receptors lie at the core of the pathological programming induced by early-life stress.
authors.affiliation: The Psychiatric Institute, Department of Psychiatry, College of Medicine, The University of Illinois at Chicago, Chicago, IL 60612, USA. fmatrisciano@hotmail.com
authors.forename: Francesco
authors.initials: F
authors.lastname: Matrisciano
authors.forename: Patricia
authors.initials: P
authors.lastname: Tueting
authors.forename: Stefania
authors.initials: S
authors.lastname: Maccari
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Guidotti
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D012149:Restraint, Physical / Q000009:adverse effects / Q000523:psychology; D012559:Schizophrenia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D013315:Stress, Psychological / Q000150:complications / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3
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