title: Omega-3 fatty acid deficiency disrupts endocytosis, neuritogenesis, and mitochondrial protein pathways in the mouse hippocampus.
abstract: Omega-3 fatty acid (n-3 FA) deficiency is an environmental risk factor for schizophrenia, yet characterization of the consequences of deficiency at the protein level in the brain is limited. We aimed to identify the protein pathways disrupted as a consequence of chronic n-3 deficiency in the hippocampus of mice. Fatty acid analysis of the hippocampus following chronic dietary deficiency revealed a 3-fold decrease (p < 0.001) in n-3 FA levels. Label free LC-MS/MS analysis identified and profiled 1008 proteins, of which 114 were observed to be differentially expressed between n-3 deficient and control groups (n = 8 per group). The cellular processes that were most implicated were neuritogenesis, endocytosis, and exocytosis, while specific protein pathways that were most significantly dysregulated were mitochondrial dysfunction and clathrin mediated endocytosis (CME). In order to characterize whether these processes and pathways are ones influenced by antipsychotic medication, we used LC-MS/MS to test the differential expression of these 114 proteins in the hippocampus of mice chronically treated with the antipsychotic agent haloperidol. We observed 23 of the 114 proteins to be differentially expressed, 17 of which were altered in the opposite direction to that observed following n-3 deficiency. Overall, our findings point to disturbed synaptic function, neuritogenesis, and mitochondrial function as a consequence of dietary deficiency in n-3 FA. This study greatly aids our understanding of the molecular mechanism by which n-3 deficiency impairs normal brain function, and provides clues as to how n-3 FA exert their therapeutic effect in early psychosis.
authors.affiliation: Department of Psychiatry, Royal College of Surgeons in Ireland, ERC Beaumont Hospital Dublin, Ireland ; Proteome Research Centre, School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College of Dublin Dublin, Ireland.
authors.forename: Jane A
authors.initials: JA
authors.lastname: English
authors.forename: Akiko
authors.initials: A
authors.lastname: Harauma
authors.forename: Melanie
authors.initials: M
authors.lastname: Föcking
authors.forename: Kieran
authors.initials: K
authors.lastname: Wynne
authors.forename: Caitriona
authors.initials: C
authors.lastname: Scaife
authors.forename: Gerard
authors.initials: G
authors.lastname: Cagney
authors.forename: Toru
authors.initials: T
authors.lastname: Moriguchi
authors.forename: David R
authors.initials: DR
authors.lastname: Cotter
keywords: Omega-3; clathrin mediated endocytosis; mitochondrial dysfunction; neuritogenesis; proteomics; schizophrenia