Preliminary evidence of neuropathology in nonhuman primates prenatally exposed to maternal immune activation

Abstract

Maternal infection during pregnancy increases the risk for neurodevelopmental disorders in offspring. Rodent models have played a critical role in establishing maternal immune activation (MIA) as a causal factor for altered brain and behavioral development in offspring. We recently extended these findings to a species more closely related to humans by demonstrating that rhesus monkeys (Macaca mulatta) prenatally exposed to MIA also develop abnormal behaviors. Here, for the first time, we present initial evidence of underlying brain pathology in this novel nonhuman primate MIA model. Pregnant rhesus monkeys were injected with a modified form of the viral mimic polyI:C (poly ICLC) or saline at the end of the first trimester. Brain tissue was collected from the offspring at 3.5 years and blocks of dorsolateral prefrontal cortex (BA46) were used to analyze neuronal dendritic morphology and spine density using the Golgi-Cox impregnation method. For each case, 10 layer III pyramidal cells were traced in their entirety, including all apical, oblique and basal dendrites, and their spines. We further analyzed somal size and apical dendrite trunk morphology in 30 cells per case over a 30μm section located 100±10μm from the soma. Compared to controls, apical dendrites of MIA-treated offspring were smaller in diameter and exhibited a greater number of oblique dendrites. These data provide the first evidence that prenatal exposure to MIA alters dendritic morphology in a nonhuman primate MIA model, which may have profound implications for revealing the underlying neuropathology of neurodevelopmental disorders related to maternal infection.

Autism spectrum disorder: neuropathology and animal models

“…MIA mice have delayed cell development in the neocortex [333] and reduced cell density and abnormal developmental migration in the cerebellum [325]. The offspring of pregnant rhesus monkeys treated with poly I:C have thinner apical dendrites with more proximal dendritic branching in the dorsolateral prefrontal cortex [383]. …”

Genes, circuits, and precision therapies for autism and related neurodevelopmental disorders

“…Other epidemiological studies have implicated activation of the maternal immune system during gestation as a contributor to the development of various neuropsychiatric disorders (17–19) and more specifically in the development of autism (19–21). Maternal immune activation leads to region specific changes in brain cytokines (22) and neuropathological changes that can be detected even in nonhuman primates (23). Interestingly, maternal immune activation is implicated in the exacerbation of syndromic forms of ASD.…”

Serum C-reactive protein in adolescence and risk of schizophrenia in adulthood: A prospective birth cohort study

“…Systematic reviews (Khandaker et al, 2012, Khandaker et al, 2013) of population-based studies suggest prenatal maternal infection (Brown et al, 2004a, Brown and Derkits, 2010, Buka et al, 2001a, Khandaker et al, 2013, Mortensen et al, 2007), raised inflammatory markers during pregnancy (Brown et al, 2004b, Buka et al, 2001b, Canetta et al, 2014), and childhood infections (Benros et al, 2011, Dalman et al, 2008, Khandaker et al, 2015b) are associated with psychotic disorders in adulthood and sub-clinical psychotic experiences (PEs) in adolescence. Similarly, infection/inflammation is associated with cognitive impairments in schizophrenia patients (Dickerson et al, 2012, Dickerson et al, 2008) and impaired neurodevelopment and behavioural problems in experimental animal models of prenatal immune activation (Meyer et al, 2008, Shi et al, 2009, Weir et al, 2015). Atopic disorder and autoimmunity, which reflect alterations in adaptive immune responses, are associated with adult schizophrenia (Eaton et al, 2006, Karlsson et al, 2012, Pedersen et al, 2012, Steiner et al, 2013) and adolescent PEs (Khandaker et al, 2014b).…”