title: Anti-NMDA receptor autoantibodies and associated neurobehavioral pathology in mice are dependent on age of first exposure to Toxoplasma gondii.
abstract: Toxoplasma gondii is a pathogen implicated in psychiatric disorders. As elevated antibodies to T. gondii are also present in non-symptomatic individuals, we hypothesized that the age during first exposure to the pathogen may affect symptom manifestation. We tested this hypothesis by evaluating neurobehavioral abnormalities and the immune response in mice following adolescent or adult T. gondii infection.
  
  
  
  Mice were infected with T. gondii at postnatal day 33 (adolescent/juvenile) or 61 (adult). At 8weeks post-infection (wpi), pre-pulse inhibition of the acoustic startle (PPI) in mice administered MK-801 (0.1 and 0.3mg/kg) and amphetamine (5 and 10mg/kg) was assessed. Peripheral (anti-T. gondii, C1q-associated IgG and anti-GLUN2 antibodies) and central (C1q and Iba1) markers of the immune response were also evaluated. In addition, regional brain expression of N-methyl-d-aspartate receptor (NMDAR) subunits (GLUN1 and GLUN2A), glutamatergic (vGLUT1, PSD95) and GABAergic (GAD67) markers, and monoamines (DA, NE, 5-HT) and their metabolites were measured.
  
  
  
  Juvenile and adult infected mice exhibited opposite effects of MK-801 on PPI, with decreased PPI in juveniles and increased PPI in adults. There was a significantly greater elevation of GLUN2 autoantibodies in juvenile-compared to adult-infected mice. In addition, age-dependent differences were found in regional expression of NMDAR subunits and markers of glutamatergic, GABAergic, and monoaminergic systems. Activated microglia and C1q elevations were found in both juvenile- and adult-T. gondii infected mice.
  
  
  
  Our study demonstrates that the age at first exposure to T. gondii is an important factor in shaping distinct behavioral and neurobiological abnormalities. Elevation in GLUN2 autoantibodies or complement protein C1q may be a potential underlying mechanism. A better understanding of these age-related differences may lead to more efficient treatments of behavioral disorders associated with T. gondii infection.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA. Electronic address: KannanG17@gmail.com.
authors.forename: Geetha
authors.initials: G
authors.lastname: Kannan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Crawford
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
authors.forename: ChunXia
authors.initials: C
authors.lastname: Yang
authors.affiliation: Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Gressitt
authors.affiliation: Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Chinezimuzo
authors.initials: C
authors.lastname: Ihenatu
authors.affiliation: Molecular Neuropsychiatry Research Branch, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Irina N
authors.initials: IN
authors.lastname: Krasnova
authors.affiliation: Molecular Neuropsychiatry Research Branch, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Jean Lud
authors.initials: JL
authors.lastname: Cadet
authors.affiliation: Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Yolken
authors.affiliation: Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Emily G
authors.initials: EG
authors.lastname: Severance
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA; Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Pletnikov
mesh_terms: D000375:Aging; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001921:Brain / Q000469:parasitology* / Q000473:pathology*; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D001523:Mental Disorders / Q000473:pathology*; D008807:Mice, Inbred BALB C; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology*; D014122:Toxoplasma; D014123:Toxoplasmosis
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Autoantibody; C1q; NMDAR; Neurodevelopment; Schizophrenia; Toxoplasma