Arachidonic Acid Drives Postnatal Neurogenesis and Elicits a Beneficial Effect on Prepulse Inhibition, a Biological Trait of Psychiatric Illnesses

Abstract

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.

Horizontal Basal Cell-Specific Deletion ofPax6Impedes Recovery of the Olfactory Neuroepithelium Following Severe Injury

“…Pax6 is a multifunctional protein that regulates the proliferation and differentiation of neural stem/progenitor cells (NSCs) in the CNS by regulating the expression of several downstream genes, including Fabp7, Ngn2, and Wnt7b [16,[34][35][36][37]. Pax6 is also expressed in astrocytes in late embryogenesis and postnatally, and deleting Pax6 causes cells to retain their NSC-like properties and inhibits astrocyte maturation [28].…”

Adult Neurogenesis and Mental Illness

“…Diminished prepulse inhibition of startle behavior, which is believed to reflect sensory gating deficits, is often described as a biological marker of schizophrenia, although it is not specific to this condition (Braff et al, 2001). Rats lacking adult neurogenesis, because of irradiation or MAM treatment, show impairments in prepulse inhibition of acoustic startle (Iwata et al, 2008;Maekawa et al, 2009). Irradiated rats also show behavioral abnormalities in social interactions and working memory that are also impaired in human schizophrenia (Iwata et al, 2008).…”

The influence of the human microbiome and probiotics on cardiovascular health

“…These effects may be direct via the probiotic, or through modulating the gut Clostridiaceae, Eubacteriaceae or other constituents. Since AA and DHA play important roles in neurogenesis, neurotransmission, and protection against oxidative stress, and their concentrations in the brain influence cognitive processes, including learning and memory, [97][98][99] the selection and application of probiotics must be carefully conceived.…”