Effects of dietary-induced alterations in rat brain docosahexaenoic acid accrual on phospholipid metabolism and mitochondrial bioenergetics: An in vivo ³¹P MRS study

Abstract

Evidence from ³¹P magnetic resonance spectroscopy (³¹P MRS) studies suggest that different psychiatric disorders, which typically emerge during adolescence and young adulthood, are associated with abnormalities in mitochondrial bioenergetics and membrane phospholipid metabolism. These disorders are also associated with deficits in omega-3 polyunsaturated fatty acids (n-3 PUFA), including docosahexaenoic acid (DHA) which accumulates in mitochondrial and synaptic membranes. The present study investigated the effects of dietary-induced alterations in brain DHA accrual during adolescence on phospholipid metabolism and bioenergetics in the adult rat brain using ³¹P MRS. During the peri-adolescent period (P21-P90), male rats were fed a diet with no n-3 fatty acids (Deficient, DEF, n = 20), a diet fortified with preformed DHA (fish oil, FO, n = 20), or a control diet fortified with alpha-linolenic acid (18:3n-3, n = 20). On P90, ³¹P MRS was performed under isoflurane anesthetic using a 7 T Bruker Biospec system. Compared with controls, brain DHA levels were significantly lower in adult rats fed the DEF diet (−17%, p ≤ 0.0001) and significantly higher in rats fed the FO diet (+14%, p ≤ 0.0001). There were no significant group differences for indices of bioenergetics, including adenosine triphosphate and phosphocreatine levels, or indices of membrane phospholipid metabolism including phosphomonoesters and phosphodiesters. Therefore, the present ³¹P MRS data suggest that rat brain DHA levels are not a significant predictor of mitochondrial bioenergetics or membrane phospholipid metabolism.

Introduction

Emerging evidence suggests that mitochondrial dysfunction and membrane phospholipid abnormalities are associated with the pathophysiology of different psychiatric disorders, including bipolar disorder, depression, and schizophrenia (Horrobin et al., 1994, Meltzer, 1991, Rezin et al., 2009, Scaini et al., 2016, Schaeffer et al., 2012). Supporting evidence has been provided by studies using phosphorous magnetic resonance spectroscopy (³¹P MRS), which measures indices of membrane phospholipid turnover and mitochondrial bioenergetics. Indices of membrane phospholipid turnover include phospholipid anabolites (i.e., phosphomonoesters, PME) and catabolites (i.e., phosphodiesters, PDE), and a reduction in the PME:PDE ratio is thought to reflect a decrease in the synthesis and/or an increase in the breakdown of membrane phospholipids. Indices of mitochondrial bioenergetics include high-energy phosphates, including phosphocreatine (PCr) and adenosine triphosphate (ATP). While ³¹P MRS studies have reported abnormalities in phospholipid metabolism and/or mitochondrial bioenergetics in patients with bipolar disorder (Yildiz et al., 2001), major depressive disorder (MDD) (Kato et al., 1992, Volz et al., 1998), and schizophrenia (Yuksel et al., 2015), the underlying risk factors remain poorly understood.

One potential risk factor is a deficiency in the omega-3 polyunsaturated fatty acid (n-3 PUFA) docosahexaenoic acid (DHA). DHA is highly concentrated in brain and preferentially accumulates in gray matter mitochondrial and synaptosomal membranes (Suzuki et al., 1997). Evidence from postmortem rat brain studies suggest that DHA modulates the activity of enzymes involved in membrane phospholipid metabolism (Rao et al., 2007) and mitochondrial ATP generation (Afshordel et al., 2015, Harbeby et al., 2012, Kitajka et al., 2004, Ximenes da Silva et al., 2002). Meta-analyses indicate that bipolar disorder (McNamara and Welge, 2016), schizophrenia (van der Kemp et al., 2012), and MDD (Lin et al., 2010) are associated with lower erythrocyte phospholipid membrane DHA levels, and preliminary clinical ³¹P MRS evidence suggests that erythrocyte membrane DHA levels were correlated with membrane phospholipid metabolism (Richardson et al., 2001). However, the relationships among brain DHA membrane levels, phospholipid metabolism, and mitochondrial bioenergetics have not been systematically evaluated by ³¹P MRS.

The objective of the present study was to use ³¹P MRS to investigate the effects of dietary-induced alterations in rat brain DHA levels on phospholipid metabolism and bioenergetics in vivo. Based on the translational evidence reviewed above, our primary hypothesis was that brain DHA levels would be positively associated with indices of mitochondrial bioenergetics and membrane phospholipid metabolism.