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

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.

Genes in immune pathways associated with abnormal white matter integrity in first-episode and treatment-naïve patients with schizophrenia

“…47 Another study showed that prenatal exposure to maternal inflammation influences the levels of N-acetylaspartate/creatine and myo-inositol/creatinine in the cingulate cortex of mice. 48 In fact, abnormal white matter microstructure in the left anterior cingulate cortex has been found in mice exposed to an immune challenge in early or late prenatal development, 49 which is consistent with our findings in the current study. Using data from the PGC-I, we found that the blue and brown modules harboured the genes predominantly related to the histone methyltransferase activity and the histone-lysine N-methyltransferase activity.…”

Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic: Mechanisms of Psychosis Risk

“…Given that the vast majority of children of mothers who experience an infection do not develop psychiatric disease, recent consideration has been given to maternal and foetal mechanisms of resilience to perinatal infection and inflammation: these include maternal nutritional status, the microbiome, and a variety of postnatal environmental factors (235). In terms of interventions within the MIA paradigm that have potential widespread relevance, dietary supplementation with omega-3 polyunsaturated fatty acids (PUFAs) may represent an attractive preventative strategy (236,237).…”

Maternal immune activation: Implications for neuropsychiatric disorders

“…Similarly, minocycline, a microglia (a type of macrophage-like cell in the brain) modulator, prevents the emergence of MIA-induced behaviors and changes in cytokines in the adult brain when given during exposure to peripubertal stress (3, 4, 75). Several SZ and ASD-related phenotypes in MIA offspring can also be prevented with probiotic treatment(72), anti-cytokine antibody treatment(19, 76), and environmental enrichment (77) or maternal dietary supplementation with zinc(78, 79), n-3 polyunsaturated fatty acids (80, 81) or N-acetyl-cysteine (NAC)(82). Finally, one of the most exciting potential treatments is anti-purinergic therapy, which completely reverses several ASD-related phenotypes in MIA offspring(4).…”