Perinatal n-3 fatty acid deficiency selectively reduces myo-inositol levels in the adult rat PFC: an in vivo

To investigate the effects of omega-3 fatty acid deficiency on phosphatidylinositol signaling in brain, myoinositol (mI) concentrations were determined in the prefrontal cortex (PFC) of omega-3 fatty acid deficient rats by in vivo proton magnetic resonance spectroscopy (H-MRS). To generate graded deficits in PFC docosahexaenoic acid (22:6n -3) (DHA) composition, perinatal and postweaning a-linolenic acid (18:3n-3) (ALA) deficiency models were used. Adult male rats were scanned in a 7T Bruker Biospec system and a H-MRS spectrum acquired from the bilateral medial PFC. Rats were then challenged with SKF83959, a selective agonist at phosphoinositide (PI)-coupled dopamine D1 receptors. Postmortem PFC fatty acid composition was determined by gas chromatography. Relative to controls, PFC DHA composition was significantly reduced in adult postweaning (227%) and perinatal (265%) ALA-deficiency groups. Basal PFC mI concentrations were significantly reduced in the perinatal deficiency group (221%, P 5 0.001), but not in the postweaning deficiency group (21%, P 5 0.86). Among all rats, DHA composition was positively correlated with mI concentrations and the mI/creatine (Cr) ratio. SKF83959 challenge significantly increased mI concentrations only in the perinatal deficiency group (116%, P 5 0.02). These data demonstrate that perinatal deficits in cortical DHA accrual significantly and selectively reduce mI concentrations and augment receptor-generated mI synthesis.—McNamara, R. K., J. Able, R. Jandacek, T. Rider, P. Tso, and D. M. Lindquist. Perinatal n-3 fatty acid deficiency selectively reduces myo-inositol levels in the adult rat PFC: an in vivo H-MRS study. J. Lipid Res. 2009. 50: 405–411. Supplementary key words proton magnetic resonance spectroscopy • omega-3 fatty acids • docosahexaenoic acid • DHA • Myo-inositol • N acetyl aspartate • prefrontal cortex Mammalian brain lipids are comprised of a ratio of saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids. The principle omega-3 polyunsaturated fatty acid found in brain is docosahexaenoic acid (22:6n-3) (DHA), which comprises approximately 15–20 percent of total fatty acid composition (1). DHA is predominantly esterified into the sn-2 position of phosphatidylethanolamine and phosphatidylserine phospholipids (2), and is mobilized by phospholipase A2 isoforms (3). Within brain tissues, DHA preferentially accumulates in neuronal growth cones, synaptosomes, astrocytes, microsomal, and mitochondrial membranes (4, 5). Because mammals are incapable of synthesizing n-3 fatty acids de novo, they are entirely dependent on dietary sources to procure and maintain adequate peripheral and central tissue composition. The dietary n-3 fatty acid precursor alpha-linolenic acid (18:3n-3) (ALA) is converted to DHA following a series of microsomal desaturation-elongation reactions mediated predominantly by the liver, and the final synthesis of DHA requires additional metabolism within peroxisomes (6). Perinatal or postweaning dietary ALA deficiency significantly reduces cortical DHA composition in the adult rat brain (7, 8). Moreover, perinatal ALA deficiency is associated with abnormalities in multiple neurotransmitter systems including dopamine and serotonin (9), and neurocognitive impairments and elevations in behavioral indices of depression, anxiety, and aggression (10). This work was supported in part by National Institute of Mental Health grants MH073704 and MH074858 to R.K.M., and DK59630 to P.T. Manuscript received 22 July 2008 and in revised form 11 September 2008 and in re-revised form 17 September 2008. Published, JLR Papers in Press, September 18, 2008. DOI 10.1194/jlr.M800382-JLR200 Abbreviations: AA, arachidonic acid (20:4n-6); ALA, alpha-linolenic acid (18:3n-3); Cho, choline; Cr, creatine; DHA, docosahexaenoic acid (22:6n-3); DPA, docosapentaenoic acid (22:5n-6); Glx, glutamine and glutamate; H-MRS, protonmagnetic resonance spectroscopy;MARCKS, myristoylated alanine-rich C kinase substrate; mI, myo -inositol; NAA, N acetyl aspartate; PFC, prefrontal cortex; PI, phosphoinositide; PLC, phospholipase C; Tau, taurine. 1 To whom correspondence should be addressed. e-mail: [email protected] The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of one table. Copyright © 2009 by the American Society for Biochemistry and Molecular Biology, Inc. This article is available online at http://www.jlr.org Journal of Lipid Research Volume 50, 2009 405 by gest, on A uust 8, 2017 w w w .j.org D ow nladed fom 0.DC1.html http://www.jlr.org/content/suppl/2008/09/25/M800382-JLR20 Supplemental Material can be found at: