Arachidonic acid drives postnatal neurogenesis and elicits a beneficial effect on prepulse inhibition, a biological trait of psychiatric illnesses.

Prepulse inhibition (PPI) is a compelling endophenotype (biological markers) for mental disorders including schizophrenia. In a previous study, we identified Fabp7, a fatty acid binding protein 7 as one of the genes controlling PPI in mice and showed that this gene was associated with schizophrenia. We also demonstrated that disrupting Fabp7 dampened hippocampal neurogenesis. In this study, we examined a link between neurogenesis and PPI using different animal models and exploring the possibility of postnatal manipulation of neurogenesis affecting PPI, since gene-deficient mice show biological disturbances from prenatal stages. In parallel, we tested the potential for dietary polyunsaturated fatty acids (PUFAs), arachidonic acid (ARA) and/or docosahexaenoic acid (DHA), to promote neurogenesis and improve PPI. PUFAs are ligands for Fabp members and are abundantly expressed in neural stem/progenitor cells in the hippocampus. Our results are: (1) an independent model animal, Pax6 (+/−) rats, exhibited PPI deficits along with impaired postnatal neurogenesis; (2) methylazoxymethanol acetate (an anti-proliferative drug) elicited decreased neurogenesis even in postnatal period, and PPI defects in young adult rats (10 weeks) when the drug was given at the juvenile stage (4–5 weeks); (3) administering ARA for 4 weeks after birth promoted neurogenesis in wild type rats; (4) raising Pax6 (+/−) pups on an ARA-containing diet enhanced neurogenesis and partially improved PPI in adult animals. These results suggest the potential benefit of ARA in ameliorating PPI deficits relevant to psychiatric disorders and suggest that the effect may be correlated with augmented postnatal neurogenesis.

前脉冲抑制（PPI）是包括精神分裂症在内的精神障碍的一种引人注目的内表型（生物学标记）。在先前的一项研究中，我们确定脂肪酸结合蛋白7（Fabp7）是控制小鼠PPI的基因之一，并表明该基因与精神分裂症有关。我们还证明，破坏Fabp7会抑制海马神经发生。在这项研究中，我们使用不同的动物模型研究了神经发生与PPI之间的联系，并探讨了出生后对神经发生的调控影响PPI的可能性，因为基因缺陷小鼠从胚胎期就表现出生物学紊乱。同时，我们测试了膳食多不饱和脂肪酸（PUFAs）、花生四烯酸（ARA）和/或二十二碳六烯酸（DHA）促进神经发生和改善PPI的潜力。PUFAs是Fabp成员的配体，在海马的神经干/祖细胞中大量表达。我们的研究结果如下：（1）一种独立的模型动物，Pax6（+/−）大鼠，表现出PPI缺陷以及出生后神经发生受损；（2）甲基氧化偶氮甲醇醋酸酯（一种抗增殖药物）即使在出生后也会引起神经发生减少，并且在幼年期（4 - 5周）给药时，年轻成年大鼠（10周）会出现PPI缺陷；（3）出生后给予ARA 4周可促进野生型大鼠的神经发生；（4）用含ARA的饮食喂养Pax6（+/−）幼崽可增强成年动物的神经发生并部分改善PPI。这些结果表明ARA在改善与精神障碍相关的PPI缺陷方面具有潜在益处，并提示这种作用可能与出生后神经发生增强有关。