Aberrant neural synchrony in the maternal immune activation model: using translatable measures to explore targeted interventions

Abstract

Maternal exposure to infection occurring mid-gestation produces a three-fold increase in the risk of schizophrenia in the offspring. The critical initiating factor appears to be the maternal immune activation (MIA) that follows infection. This process can be induced in rodents by exposure of pregnant dams to the viral mimic Poly I:C, which triggers an immune response that results in structural, functional, behavioral, and electrophysiological phenotypes in the adult offspring that model those seen in schizophrenia. We used this model to explore the role of synchronization in brain neural networks, a process thought to be dysfunctional in schizophrenia and previously associated with positive, negative, and cognitive symptoms of schizophrenia. Exposure of pregnant dams to Poly I:C on GD15 produced an impairment in long-range neural synchrony in adult offspring between two regions implicated in schizophrenia pathology; the hippocampus and the medial prefrontal cortex (mPFC). This reduction in synchrony was ameliorated by acute doses of the antipsychotic clozapine. MIA animals have previously been shown to have impaired pre-pulse inhibition (PPI), a gold-standard measure of schizophrenia-like deficits in animal models. Our data showed that deficits in synchrony were positively correlated with the impairments in PPI. Subsequent analysis of LFP activity during the PPI response also showed that reduced coupling between the mPFC and the hippocampus following processing of the pre-pulse was associated with reduced PPI. The ability of the MIA intervention to model neurodevelopmental aspects of schizophrenia pathology provides a useful platform from which to investigate the ontogeny of aberrant synchronous processes. Further, the way in which the model expresses translatable deficits such as aberrant synchrony and reduced PPI will allow researchers to explore novel intervention strategies targeted to these changes.

The Poly(I:C)-induced maternal immune activation model in preclinical neuropsychiatric drug discovery

“…Striatal dopamine level reductions reported in Poly(I:C) MIA offspring (Ozawa et al, 2006) are sensitive to antipsychotic treatment (Zuckerman et al, 2003). Alterations to proper cortical functioning in adult offspring from Poly(I:C) MIA and neural synchrony disturbances between the Hipp and PFC, associated with schizophrenia, have been identified in the Poly(I:C) MIA animal model (Zhang et al, 2012;Dickerson & Bilkey, 2013). Compromised levels of dopamine (Bitanihirwe et al, 2010), and serotonin (Winter et al, 2009) are reported in the NAc, Hipp, and PFC and changes in levels of GABA are reported in the Hipp and Amyg (Nyffeler et al, 2006b) 2007).…”

“…Further, acute treatment with clozapine, the first atypical antipsychotic drug available, was reported to reverse impaired long-range neural synchrony between the hippocampus and medial prefrontal cortex (mPFC), a particular functional deficit observed in the Poly(I:C) MIA rat model which is associated with the presentation of schizophrenialike behavior (Dickerson & Bilkey, 2013). The effect of clozapine on the reduced coupling between the mPFC and the hippocampus may contribute to its therapeutic effects in schizophrenia, and the Poly(I:C) MIA model may serve as a tool to investigate the molecular changes underlying the observed functional deficits, potentially leading to the exploration of novel intervention strategies targeting these molecules (Dickerson & Bilkey, 2013).…”

“…Concerning gene × environment interactions as the biological interface for the long-established "nature versus nurture" etiological principle, the Poly(I:C) MIA model has contributed to the elucidation of some of the key players involved in the pathogenesis of schizophrenia (Ozawa et al, 2006;Dickerson & Bilkey, 2013;Van den Eynde et al, 2013). For example, following Poly(I:C)-assisted MIA, mice with mutations in the Disrupted in Schizophrenia 1 gene (DISC1) -originally identified in a case of familial human schizophrenia (Chubb et al, 2008;Jaaro-Peled et al, 2009) -display higher susceptibility to the development of behavioral features associated with schizophrenia (Lipina et al, 2013).…”

“…1). While LPS and Poly(I:C) elicit distinct molecular profiles -targeting the toll-like receptor (TLR) 4 and TLR3 pathways respectively -both MIA paradigms have been successfully used to establish animal models for some of the most common and debilitating neuropsychiatric disorders, including schizophrenia, autism and depression (Fatemi et al, 1999;Fatemi et al, 2002aFatemi et al, , 2002bFatemi et al, 2002b;Smith et al, 2007;Garbett et al, 2012;Dickerson & Bilkey, 2013;Bauman et al, 2014;Khan et al, 2014). Despite continuous efforts, the neurobiological basis of these severe mental illnesses, which compromise the quality of life of patients and their families as well as posing significant socioeconomic burden on society (Kessler et al, 2003), remain incompletely understood currently available pharmacotherapeutic options present with major limitations: they provide relief from only some of the symptoms and fail to cure the respective disorders, are effective only in a limited number of affected patients, Fig.…”

“…The normal course of fetal development requires a specific balance between the maternal and fetal environments of constitutively expressed cytokines -small pleiotropic signaling molecules released as part of the innate immune response -with the placenta constituting the structural interface for maternal-fetal-immune interaction (Mehler & Kessler, 1998;Cannon et al, 2002;Deverman & Patterson, 2009;Dickerson & Bilkey, 2013;Garay et al, 2013). In the case of hemochorial placentation, the type of placentation occurring in mammals including humans and rodents, the placenta allows for direct contact between the maternal and fetal compartments (Colucci et al, 2011), and fetal syntiotrophoblast cells are exposed to mediators of the maternal immune response (Moffett & Loke, 2006).…”