Dietary Docosahexaenoic Acid Supplementation Modulates Hippocampal Development in the Pemt−/− Mouse

Abstract

The development of fetal brain is influenced by nutrients such as docosahexaenoic acid (DHA, 22:6) and choline. Phosphatidylethanolamine-N-methyltransferase (PEMT) catalyzes the biosynthesis of phosphatidylcholine from phosphatidylethanolamine enriched in DHA and many humans have functional genetic polymorphisms in the PEMT gene. Previously, it was reported that Pemt ؊/؊ mice have altered hippocampal development. The present study explores whether abnormal phosphatidylcholine biosynthesis causes altered incorporation of DHA into membranes, thereby influencing brain development, and determines whether supplemental dietary DHA can reverse some of these changes. Pregnant C57BL/6 wild type (WT) and Pemt ؊/؊ mice were fed a control diet, or a diet supplemented with 3 g/kg of DHA, from gestational day 11 to 17. Brains from embryonic day 17 fetuses derived from Pemt ؊/؊ dams fed the control diet had 25-50% less phospholipid-DHA as compared with WT (p < 0.05). Also, they had 60% more neural progenitor cell proliferation (p < 0.05), 60% more neuronal apoptosis (p < 0.01), and 30% less calretinin expression (p < 0.05; a marker of neuronal differentiation) in the hippocampus compared with WT. The DHA-supplemented diet increased fetal brain Pemt ؊/؊ phospholipid-DHA to WT levels, and abrogated the neural progenitor cell proliferation and apoptosis differences. Although this diet did not change proliferation in the WT group, it halved the rate of apoptosis (p < 0.05). In both genotypes, the DHA-supplemented diet increased calretinin expression 2-fold (p < 0.05). These results suggest that the changes in hippocampal development in the Pemt ؊/؊ mouse could be mediated by altered DHA incorporation into membrane phospholipids, and that maternal dietary DHA can influence fetal brain development.

Essential fatty acids and their metabolites as modulators of stem cell biology with reference to inflammation, cancer, and metastasis

“…Similarly, ω-3 fatty acids were found to impact hematopoietic differentiation by reducing myeloid progenitor cell frequency in the bone marrow and promoting progenitor cell differentiation [34,35]. These results [29][30][31][32][33][34][35] suggest that PUFAs play a significant role in stem cell biology and possibly interact with other biomolecules involved in stem cell survival, proliferation, and differentiation as discussed below.…”

“…Furthermore, dietary administration of docosahexaenoic acid significantly increased the number of 5-bromo-2′-deoxyuridine(+)/NeuN(+) newborn neurons in the granule cell layer of the dentate gyrus in adult rats, suggesting that DHA effectively promotes neurogenesis both in vitro and in vivo, and thus, modulates hippocampal function [32,33]. Similarly, ω-3 fatty acids were found to impact hematopoietic differentiation by reducing myeloid progenitor cell frequency in the bone marrow and promoting progenitor cell differentiation [34,35].…”

Nutrigenómica: Revelando Los Aspectos Moleculares De Una Nutrición Personalizada

“…Además, el DHA inhibe la expresión del RNAm de CD4 y CD25 mediante señales extracelulares reguladas por kinasas (38). Adicionalmente, permite la regulación de genes para el desarrollo del hipocampo (39). Se ha observado que una menor actividad del gen que expresa la enzima fosfatidil etanolamina-N-metiltransferasa (PEMT), produce una menor incorporación de DHA a los fosfolípidos de las células del hipocampo (39).…”

“…Adicionalmente, permite la regulación de genes para el desarrollo del hipocampo (39). Se ha observado que una menor actividad del gen que expresa la enzima fosfatidil etanolamina-N-metiltransferasa (PEMT), produce una menor incorporación de DHA a los fosfolípidos de las células del hipocampo (39). Hoy se sabe que el gen de PEMT presenta un gran polimorfismo, lo que implica una respuesta no uniforme al DHA y por lo tanto una incorporación variable del ácido graso a los fosfolípidos del hipocampo, modificando la función de este segmento cerebral (39).…”

Prophylactic combined supplementation of choline and docosahexaenoic acid attenuates vascular cognitive impairment and preserves hippocampal cell viability in rat model of chronic cerebral hypoperfusion ischemic brain injury

“…32 Moreover, studies have also shown that a higher choline intake increases PEMT activity resulting in greater PC-DHA enrichment of the PC molecule whereas higher DHA intake in the absence of PEMT activity as in PEMT-/-mice influences PC-DHA, PS-DHA, and PI DHA that restores fetal hippocampal neurogenesis. 33 Thus with increased prophylactic availability of both choline-DHA and greater PC-DHA enrichment of the PC molecule, neural membranes may be largely better stabilized to withstand injurious effects of chronic cerebral hypoperfusion and promote neuronal repair by enhancing neural plasticity, neurogenesis that might attenuate cognitive deficits.…”