title: Maternal influenza viral infection causes schizophrenia-like alterations of 5-HT₂A and mGlu₂ receptors in the adult offspring.
abstract: Epidemiological studies indicate that maternal influenza viral infection increases the risk for schizophrenia in the adult offspring. The serotonin and glutamate systems are suspected in the etiology of schizophrenia, as well as in the mechanism of action of antipsychotic drugs. The effects of hallucinogens, such as psilocybin and mescaline, require the serotonin 5-HT(2A) receptor, and induce schizophrenia-like psychosis in humans. In addition, metabotropic glutamate receptor mGlu(2/3) agonists show promise as a new treatment for schizophrenia. Here, we investigated the level of expression and behavioral function of 5-HT(2A) and mGlu(2) receptors in a mouse model of maternal influenza viral infection. We show that spontaneous locomotor activity is diminished by maternal infection with the mouse-adapted influenza A/WSN/33 (H1N1) virus. The behavioral responses to hallucinogens and glutamate antipsychotics are both affected by maternal exposure to influenza virus, with increased head-twitch response to hallucinogens and diminished antipsychotic-like effect of the glutamate agonist. In frontal cortex of mice born to influenza virus-infected mothers, the 5-HT(2A) receptor is upregulated and the mGlu(2) receptor is downregulated, an alteration that may be involved in the behavioral changes observed. Additionally, we find that the cortical 5-HT(2A) receptor-dependent signaling pathways are significantly altered in the offspring of infected mothers, showing higher c-fos, egr-1, and egr-2 expression in response to the hallucinogenic drug DOI. Identifying a biochemical alteration that parallels the behavioral changes observed in a mouse model of prenatal viral infection may facilitate targeting therapies for treatment and prevention of schizophrenia.
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: José L
authors.initials: JL
authors.lastname: Moreno
authors.forename: Mitsumasa
authors.initials: M
authors.lastname: Kurita
authors.forename: Terrell
authors.initials: T
authors.lastname: Holloway
authors.forename: Javier
authors.initials: J
authors.lastname: López
authors.forename: Richard
authors.initials: R
authors.lastname: Cadagan
authors.forename: Luis
authors.initials: L
authors.lastname: Martínez-Sobrido
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: Javier
authors.initials: J
authors.lastname: González-Maeso
mesh_terms: D000818:Animals; D005260:Female; D051379:Mice; D011247:Pregnancy; D014150:Antipsychotic Agents / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D018698:Glutamic Acid / Q000031:analogs & derivatives; D006213:Hallucinogens / Q000494:pharmacology; D053118:Influenza A Virus, H1N1 Subtype; D008431:Maternal-Fetal Exchange; D009434:Neural Pathways / Q000187:drug effects; D009976:Orthomyxoviridae Infections / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D012559:Schizophrenia / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D051766:Early Growth Response Protein 1; D051767:Early Growth Response Protein 2; C486109:Egr1 protein, mouse; C497327:Egr2 protein, mouse; D018698:Glutamic Acid; D006213:Hallucinogens; C108822:metabotropic glutamate receptor 2; D016760:Proto-Oncogene Proteins c-fos; D044402:Receptor, Serotonin, 5-HT2A; D018094:Receptors, Metabotropic Glutamate