Dietary supplementation with n-3 fatty acids from weaning limits brain biochemistry and behavioural changes elicited by prenatal exposure to maternal inflammation in the mouse model

Q Li,Y O Leung,X Zhang,P Basil,E X Wu,S E Chua,P C Sham,L C Ho,W Kong,A C K Law,G M Mcalonan,I Zhou,R Wei,S Lam

doi:10.1038/tp.2015.126

Abstract

Prenatal exposure to maternal immune activation (MIA) increases the risk of schizophrenia and autism in the offspring. The MIA rodent model provides a valuable tool to directly test the postnatal consequences of exposure to an early inflammatory insult; and examine novel preventative strategies. Here we tested the hypotheses that behavioural differences in the MIA mouse model are accompanied by in vivo and ex vivo alterations in brain biochemistry; and that these can be prevented by a post-weaning diet enriched with n-3 polyunsaturated fatty acid (PUFA). The viral analogue PolyI:C (POL) or saline (SAL) was administered to pregnant mice on gestation day 9. Half the resulting male offspring (POL=21; SAL=17) were weaned onto a conventional lab diet (n-6 PUFA); half were weaned onto n-3 PUFA-enriched diet. In vivo magnetic resonance spectroscopy measures were acquired prior to behavioural tests; glutamic acid decarboxylase 67 (GAD67) and tyrosine hydroxylase protein levels were measured ex vivo. The main findings were: (i) Adult MIA-exposed mice fed a standard diet had greater N-acetylaspartate/creatine (Cr) and lower myo-inositol/Cr levels in the cingulate cortex in vivo. (ii) The extent of these metabolite differences was correlated with impairment in prepulse inhibition. (iii) MIA-exposed mice on the control diet also had higher levels of anxiety and altered levels of GAD67 ex vivo. (iv) An n-3 PUFA diet prevented all the in vivo and ex vivo effects of MIA observed. Thus, n-3 PUFA dietary enrichment from early life may offer a relatively safe and non-toxic approach to limit the otherwise persistent behavioural and biochemical consequences of prenatal exposure to inflammation. This result may have translational importance.

Highlights

Schizophrenia and autism spectrum conditions are highly heritable, but environmental factors, such as exposure to maternal immune activation (MIA) in prenatal life, are thought to increase risk.[1,2,3,4]. This epidemiological evidence has lead to the development of animal models and we, and others, have reported that MIA triggered by the viral analogue PolyI:C (POL) precipitates a brain and behavioural phenotype in rodent offspring which mirrors that observed in schizophrenia and related neurodevelopmental conditions such as autism.[5,6,7,8,9,10]
We believe this study provides the first evidence that postnatal behavioural differences in offspring exposed to prenatal POL are accompanied by metabolite differences in the cingulate cortex; and that both the behavioural and metabolite sequelae can be limited by an n-3 polyunsaturated fatty acid (PUFA)-enriched diet from adolescence
MIA-exposed mice were more anxious in the elevated plus maze. These in vivo differences were accompanied by ex vivo differences in glutamic acid decarboxylase 67 (GAD67)—an increase in the prefrontal cortex and a decrease in the striatum of mice exposed to MIA

Summary

Introduction

Schizophrenia and autism spectrum conditions are highly heritable, but environmental factors, such as exposure to maternal immune activation (MIA) in prenatal life, are thought to increase risk.[1,2,3,4] This epidemiological evidence has lead to the development of animal models and we, and others, have reported that MIA triggered by the viral analogue PolyI:C (POL) precipitates a brain and behavioural phenotype in rodent offspring which mirrors that observed in schizophrenia and related neurodevelopmental conditions such as autism.[5,6,7,8,9,10] the MIA model is a well-established experimental manipulation, behaviour testing is generally the only in vivo measure acquired and the underlying biochemical alterations in this model are inferred largely from ex vivo study. Proton magnetic resonance spectroscopy (1H MRS), permits the potential relationship between brain metabolites and behaviour to be studied in the same living animal. MRS studies in patient populations have yielded much information about brain chemistry in the living brain, it is not known whether prenatal inflammation is a risk factor for such changes. We first wished to establish whether in vivo changes in brain metabolites similar to those reported in the clinical condition are caused by prenatal inflammation; and asked if these are correlated with behavioural differences

Results

Discussion

Conclusion