19445
N-3 Polyunsaturated Fatty Acid Supplementation Prevents Adult Brain Biochemistry and Behavioral Changes Elicited By Prenatal Exposure to Maternal Inflammation
Maternal immune activation (MIA) model precipitates a brain and behavioural phenotype which mirrors that observed in autism and related neurodevelopmental conditions. However, whether MIA also causes in-vivo differences in brain metabolites of exposed offspring similar to those reported in individuals with neurodevelopmental disorders; and whether such differences can be prevented is not yet known. Therefore, in this study we tested the hypothesis that there are metabolite differences, and specifically differences in N-acetyl aspartate (NAA), in the anterior cingulate cortex in offspring exposed to MIA model. However, small animal MRS does not yet permit reliable measurement of γ-aminobutyric acid (GABA). Hence we used western blot to quantify levels of GAD67 in the prefrontal cortex and striatum of this model and the effects of dietary supplementation on this marker. Last, we examined possible functional consequences of n-3 PUFA supplementation in a range of behavioural paradigms known to be altered in the adult MIA model, namely: prepulse inhibition of startle (PPI); the elevated plus maze; open field activity and response to amphetamine.
Objectives:
To test whether n-3 polyunsaturated fatty acid supplementation prevents adult brain biochemistry and behavioral changes elicited by prenatal exposure to maternal inflammation.
Methods:
We used a standard mouse MIA model generated using the viral analogue PolyI:C (POL) or saline control (SAL) administered to pregnant mice on gestation day 9. The resulting offspring were weaned and sexed at the postnatal day 35. Mice were then randomly divided and fed diets enriched with n-3 polyunsaturated fatty acids (n-3 PUFAs) or the control diet (with greater proportion of n-6 polyunsaturated fatty acids, n-6 PUFAs) until the end of the study. Non-invasive proton magnetic resonance spectroscopy (1H MRS) measures were also acquired from the majority of these animals (n6-SAL=10, n6-POL=7, n3-SAL=6, n3-POL=8) to quantify metabolic alterations in brain. Male offspring (n6-SAL=13, n6-POL=9, n3-SAL=8, n3-POL=8) were used in the behavioral tests and GAD67 western blot analysis.
Results:
NAA/Cr was significantly increased in adult mice exposed to prenatal PolyI:C challenge; n-3 PUFA supplementation from weaning suppressed this elevation. mIns/Cr was significantly decreased in the PolyI:C exposed offspring and n-3 PUFA appeared to attenuate this alteration, though this did not reach statistical significance post-hoc. In addition, n-3 PUFA appears to attenuate deficits in prepulse inhibition and anxiety behavior in the immune-challenged offspring. This was accompanied by differences in GAD67 – an increase in prefrontal cortex and decrease in dorsal and ventral striatum in mice exposed to MIA. These same animals had behavioural deficits, including impaired PPI, greater anxiety in the plus maze and sensitivity to amphetamine challenge. n-3 PUFA supplementation from weaning attenuated all these differences in the POL group.
Conclusions:
These experiments provide preliminary experimental evidence for a potential benefit of n-3 PUFA in some aspects of Neurodevelopmental disorders. However, further study of the molecular mechanisms operating in n-3 PUFA effects is warranted and this may open new avenues for prevention in neurodevelopmental psychiatric disorders.