Prenatal Immune Challenge Is an Environmental Risk Factor for Brain and Behavior Change Relevant to Schizophrenia: Evidence from MRI in a Mouse Model

Abstract

ObjectivesMaternal infection during pregnancy increases risk of severe neuropsychiatric disorders, including schizophrenia and autism, in the offspring. The most consistent brain structural abnormality in patients with schizophrenia is enlarged lateral ventricles. However, it is unknown whether the aetiology of ventriculomegaly in schizophrenia involves prenatal infectious processes. The present experiments tested the hypothesis that there is a causal relationship between prenatal immune challenge and emergence of ventricular abnormalities relevant to schizophrenia in adulthood.MethodWe used an established mouse model of maternal immune activation (MIA) by the viral mimic PolyI:C administered in early (day 9) or late (day 17) gestation. Automated voxel-based morphometry mapped cerebrospinal fluid across the whole brain of adult offspring and the results were validated by manual region-of-interest tracing of the lateral ventricles. Parallel behavioral testing determined the existence of schizophrenia-related sensorimotor gating abnormalities.ResultsPolyI:C-induced immune activation, in early but not late gestation, caused marked enlargement of lateral ventricles in adulthood, without affecting total white and grey matter volumes. This early exposure disrupted sensorimotor gating, in the form of prepulse inhibition. Identical immune challenge in late gestation resulted in significant expansion of 4th ventricle volume but did not disrupt sensorimotor gating.ConclusionsOur results provide the first experimental evidence that prenatal immune activation is an environmental risk factor for adult ventricular enlargement relevant to schizophrenia. The data indicate immune-associated environmental insults targeting early foetal development may have more extensive neurodevelopmental impact than identical insults in late prenatal life.

Behavioral alterations in rat offspring following maternal immune activation and ELR-CXC chemokine receptor antagonism during pregnancy: Implications for neurodevelopmental psychiatric disorders

“…Prepulse inhibition (PPI), a measure of sensorimotor gating, is impaired in schizophrenia patients (Braff et al, 2001) and the offspring of rats and mice treated with polyI:C during pregnancy (Dickerson et al, 2010;Howland et al, 2012;Klein et al, 2013;Mattei et al, 2014;Meyer et al, 2010;Shi et al, 2003;Smith et al, 2007;Wolff and Bilkey, 2008;Wolff and Bilkey, 2010; see also Fortier et al, 2007;Li et al, 2009). Impaired visual learning and memory is a cognitive symptom of schizophrenia identified by the MATRICS initiative (Marder and Fenton, 2004).…”

A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse

“…The procedures and testing parameters for the PPI test used here followed those described previously [29]. Two standard acoustic startle chambers for mice (SR-LAB, San Diego Instruments, San Diego, CA, USA) generated the continuous background noise of 65 dB and white noise stimuli.…”

“…Although PPI deficits have been reported in higher functioning adults with ASD [68] or Asperger"s Disorder [69], equivocal PPI findings have been reported in lower functioning children and adolescents [70] and in a cohort of individuals with both high-and low functioning individuals with ASD [71]. A higher dose of VPA in late gestation has been reported to alter PPI [67], however other late gestation exposures which may increase risk of ASD -specifically maternal immune activation -do not disrupt PPI either [28][29][30]. Thus, a PPI impairment is not always a consequence of exposure to ASD risks.…”

“…For example, we and others have reported that exposure to maternal immune activation (MIA) in early or late gestation precipitates a distinct phenotype in terms of both nature and severity [28][29][30]. In the VPA model, the embryotoxicity of VPA initially came to light because it induced neural tube defects.…”

Linking Stress and Schizophrenia: A Focus on Prepulse Inhibition

“…While administration of poly I:C to pregnant rodents can result in increased levels of cytokines in fetal brain, it only generates a non-specific immune response, without particular anti-viral antibodies (for references, see Markham & Koenig, 2011). With respect to PPI, treatment of p r e g n a n t m i c e o r r a t s w i t h p o l y I : C g e n e rates offspring that shows an impaired PPI response from post pubertal age (Ozawa et al, 2006;Li et al, 2009b;Piontkewitz et al, 2009;Vuillermot et al, 2010), which is presumably mediated by dopaminergic maldevelopment (Ozawa et al, 2006;Vuillermot et al, 2010). Thus, animal models of prenatal maternal infection show altered fetal brain development and disrupted PPI in adult offspring, probably mediated by the maternal immune response.…”