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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.
AuthorsJosé L Moreno, Mitsumasa Kurita, Terrell Holloway, Javier López, Richard Cadagan, Luis Martínez-Sobrido, Adolfo García-Sastre, Javier González-Maeso
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 31 Issue 5 Pg. 1863-72 (Feb 02 2011) ISSN: 1529-2401 [Electronic] United States
PMID21289196 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antipsychotic Agents
  • Early Growth Response Protein 1
  • Early Growth Response Protein 2
  • Egr1 protein, mouse
  • Egr2 protein, mouse
  • Hallucinogens
  • Proto-Oncogene Proteins c-fos
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • Glutamic Acid
Topics
  • Adult Children
  • Animals
  • Antipsychotic Agents (pharmacology)
  • Cerebral Cortex (metabolism)
  • Disease Models, Animal
  • Down-Regulation (drug effects)
  • Early Growth Response Protein 1 (metabolism)
  • Early Growth Response Protein 2 (metabolism)
  • Female
  • Frontal Lobe (metabolism)
  • Glutamic Acid (analogs & derivatives)
  • Hallucinogens (pharmacology)
  • Influenza A Virus, H1N1 Subtype
  • Maternal-Fetal Exchange
  • Mice
  • Neural Pathways (drug effects)
  • Orthomyxoviridae Infections (metabolism, physiopathology, virology)
  • Pregnancy
  • Proto-Oncogene Proteins c-fos (metabolism)
  • Receptor, Serotonin, 5-HT2A (drug effects, metabolism)
  • Receptors, Metabotropic Glutamate (metabolism)
  • Schizophrenia (metabolism)
  • Up-Regulation (drug effects)

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