Using a maternal immune stimulation model of schizophrenia to study behavioral and neurobiological alterations over the developmental course

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Abstract

A growing body of evidence sheds light on the neurodevelopmental nature of schizophrenia with symptoms typically emerging during late adolescence or young adulthood. We compared the pre-symptomatic adolescence period with the full symptomatic period of adulthood at the behavioral and neurobiological level in the poly I:C maternal immune stimulation (MIS) rat model of schizophrenia. We found that in MIS-rats impaired sensorimotor gating, as reflected in disrupted prepusle inhibition (PPI), emerged post-pubertally, with behavioral deficits being only recorded in adulthood but not during adolescence. Using post mortem HPLC we found that MIS-rats show distinct dopamine and serotonin changes in the medial prefrontal cortex (mPFC), nucleus accumbens (Nacc), caudate putamen, globus pallidus, and hippocampus. Further, FDG-PET has shown that these animals had lower glucose uptake in the ventral hippocampus and PFC and a higher metabolism in the amygdala and Nacc when compared to controls. Changes in neurotransmission and metabolic activity varied across brain structures with respect to first appearance and further development. In the mPFC and Hipp, MIS-rats showed abnormal neurochemical and metabolic activity prior to and with the development of behavioral deficits in both adolescent and adult states, reflecting an early impairment of these regions. In contrast, biochemical alteration in the Nacc and globus pallidus developed as a matter of age. Our findings suggest that MIS-induced neurochemical and metabolic changes are neurodevelopmental in nature and either progressive or non-progressive and that the behavioral deficits manifest as these abnormalities increase.

Introduction

Converging evidence from epidemiology, neuroimaging and post-mortem studies suggests that schizophrenia is a neurodevelopmental disorder with disruptions to early brain development interacting with peri-adolescent brain maturation and leading to aberrant behavior, typically emerging during late adolescence or young adulthood. Although this postnatal delay is a characteristic feature of schizophrenia, the exact course and neurobiological level of the maldevelopment are not fully understood. Animal models serve as important tools for identifying and studying neurobiological alterations from early age to full symptom manifestation. However, only few experimental preclinical approaches consider developmental aspects.

Based on the observations that prenatal exposure to infection constitutes a risk factor for schizophrenia, animal models implicating maternal immune stimulation (MIS) have been established. Exposing pregnant rodents to the viral mimic polyriboinosinic-polyribocytidilic acid (poly I:C) is a commonly used neurodevelopmental approach to model schizophrenia. In this model, MIS results in the emergence of myriad of behavioral, neurochemical and brain structural abnormalities in the offspring, all related to schizophrenia (Meyer and Feldon, 2012). Previous studies (Piontkewitz et al., 2012) have demonstrated that the behavioral abnormalities induced by poly I:C first emerge in adulthood, resembling the developmental delay of symptom manifestation observed in the clinic. In contrast, neuropathological alterations have been detected at different time points. While some are seen during adolescence and predate behavioral deficits (i.e. reduced hippocampal volumes and neurogenesis), others are first observed in adulthood (i.e. enlarged lateral ventricles and reduced prefrontal cortex volumes) (Piontkewitz et al., 2009). It was this progressive nature of brain abnormalities that led clinicians and scientists to administer atypical antipsychotic drugs prior to the full manifestation of symptoms in an attempt to halt disease progression (McGlashan et al., 2006, Piontkewitz et al., 2009).

In this study, we were interested in comparing behavioral and neurobiological characteristics of pre-symptomatic adolescents with the full symptomatic period of adulthood using offspring of MIS rats. More specifically, we sought to study the protracted emergence of a schizophrenia related behavior (i.e. deficits in sensorimotor gating as reflected in disrupted prepulse inhibition), along with the development of abnormal brain activity patterns using 18 fluoro desoxyglucose positron emission tomography (FDG-PET) and changes in neurotransmitter levels using post mortem HPLC.

Section snippets

Animals

Adolescent (post natal day (PND) 35 and 60) and adult (PND100) male Wistar rats were housed 2–4/cage in a temperature and humidity controlled vivarium with a 12-h light–dark cycle and with ad lib food and water. Experiments were performed during day time, according to the guidelines of the European Union Council Directive 2010/63/EU for care of laboratory animals and were approved by the local ethic committee (Regierungspräsidium Dresden, Germany for behavioral and biochemical studies and

PPI

A significant difference was found in saline offspring (F(2,29) = 13.794, p < 0.001) but not in poly I:C offspring (F(2,29) = 0.059, p = 0.943), such that higher levels of PPI were apparent at PND100 when compared to PND60 and 35. Furthermore, a significant difference was found between poly I:C and saline offspring at PND100 (t(3.84), p = 0.001) but not at PND35 (t(- 1.76), p = 0.09) or PND60 (t(0.325), p = 0.74). At PND100, poly I:C offspring exhibited lower levels of PPI when compared to saline offspring (

Discussion

In recent years there has been a growing body of evidence pointing to neurotransmission and network abnormalities in schizophrenia. However, most of the data derived from patients is confounded by heterogeneous symptom profile, medication status and disease history. Animal models may overcome this limitation. In line with previous demonstrations of abnormal brain volumetric trajectories underlying delayed symptom manifestation in poly I:C offspring, we were now able to demonstrate that MIS

Role of the Funding Source

The Funding Source had no role in study design, in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

RH: Conducted and analyzed behavioral and biochemical studies, wrote ms.

MSM: Conducted FDG-PET studies, contributed to discuss data for ms.

TG: Contributed to conducting behavioral studies.

FW and RS: Conducted biochemical analysis.

CH and IW: Contributed to design of experiments and writing ms.

MD: Contributed to design and analysis of FDG-PET study.

JP: Designed and analyzed FDG-PET study.

CW: Designed study, wrote ms, analyzed behavioral and biochemical analysis.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgments

This research was conducted under the EraNet Neuron framework (DBS_F20rat) and supported by the Federal Ministry of Education and Research, Germany (BMBF 01EW1103), Ministerio de Ciencia e Innovación (PI11/00616, PI10/02986, PI14/00860 TEC2010-21619-C04-01), Comunidad de Madrid, Fundación Mapfre, and the Canadian Institutes of Health Research. RH and FW are financed by the German Research Foundation (DFG PAK 591 (WI 2140/2-1) and DFG KFO 247 (WI 2140/1-1+2)).

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