Docosahexaenoic acid (DHA), an essential fatty acid for the proper functioning of neuronal cells: their role in mood disorders


  • Alfonso Valenzuela B Centre of Lipids, INTA, University of Chile, Santiago



Brain phospholipids, Docosahexaenoic acid, Mood disorders, Neural function


The brain and the nervous system are tissues with high contents of two polyunsaturated fatty acids: arachidonic acid (20:4, omega-6, AA) and docosahexaenoic acid (22:6, omega-3, DHA). Despite their abundance in these tissues, AA and DHA cannot be re-synthesized in mammals. However, the concentration of these fatty acids can be modulated by dietary intake. AA and DHA must be provided by the diet as such (preformed) or through the respective omega-6 and omega-3 precursors from vegetable origin. Linoleic acid, the precursor of AA is very abundant in the western diet and therefore the formation of AA from linoleic acid is not restrictive. On the other hand, alpha linolenic acid, the precursor of DHA is less available in our diet and preformed DHA is highly restrictive in some populations. During the last period of gestation and during the early post natal period, neurodevelopment occurs exceptionally quickly, and significant amounts of omega-6 and omega-3 polyunsaturated fatty acids, especially DHA, are critical to allow neurite outgrowth and the proper brain and retina development and function. In this review various functions of DHA in the nervous system, its metabolism into phospholipids, and its involvement in different neurological and mood disorders, such as Alzheimer’s disease, depression, and others are revised.


Download data is not yet available.


Ahmad A, Moriguchi T, Salem N. 2002. Decrease in neuron size in docosahexaenoic acid-deficient brain. Pediatr. Neurol. 26, 210-218. doi:10.1016/S0887-8994(01)00383-6

Aid S, Vancassel S, Poumes-Ballihaut C, Chalon S, Guesnet P, Lavialle M. 2003. Effect of a diet-induced n-3 PUFA depletion on cholinergic parameters n the rat hippocampus. J. Lipid Res. 44, 1545-1551. doi:10.1194/jlr.M300079-JLR200

Araki W, Wurtman R J. 1998. How is membrane phospholipids biosynthesis controlled in neural tissues? J. Neurosci. Res. 51, 667-674. doi:10.1002/(SICI)1097-4547(19980315)51:6<667::AID-JNR1>3.0.CO;2-9

Arvindakshan M, Ghate M, Ranjekar P, Evans D, Mahadik SP. 2003. Supplementation with a combination of omega-3 fatty acids and antioxidants (vitamin E and C) improves the outcome of schizophrenia. Schizophr. Res. 62, 195-204. doi:10.1016/S0920-9964(02)00284-0

Astorg P, Curtois A, Bertrais S, Arnault N, Meneton P, Guesnet P, Alessandri J M, Galan P, Hercberg S. 2008. Association of fish oil and long-chain n-3 polyunsaturated fatty acid intakes with the occurrence of depressive episodes in middle-aged French man and women. Prostaglandin Leukot. Essent. Fatty Acids 78, 171-182. doi:10.1016/j.plefa.2008.01.003

Barcelo-Coblijn G, Hogyes E, Kitajka K, Puskas L G, Zvara A. 2003. Modification by docosahexaenoic acid of age-induced alterations in gene expression and molecular composition of rat brain phospholipids. Proc. Natl. Acad. Sci. USA. 100, 11321-11326. doi:10.1073/pnas.1734008100

Benatti P, Peluso G, Nicolai R, Calvani M. 2004. Polyunsaturated fatty acids: biochemical, nutricional and epigenetic properties. J. Am. Col. Nutr. 23, 281- 302.

Berson EL, Rosner B, Sandberg M, Weigel-DiFranco C, Moser A, Brockhurst R, Hayes K, Johnson C, Anderson E, Gaudio A, Willett W, Schaefer E. 2004. Further evaluation of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment. Arch. Ophthamol. 122, 1306-1314. doi:10.1001/archopht.122.9.1306

Bougham JA, Conneally PM, Nance WE. 1980. Population genetic studies of retinitis pigmentosa. Am. J. Hum. Genet. 32, 223-235.

Breckenridge W C, Gombos G, Morgan IG. 1972. The lipid composition of adult rat brain synaptosomal plasma membranes. Biochim. Biophys. Acta 266, 695-707. doi:10.1016/0005-2736(72)90365-3

Calderon F, Kim HY. 2004. Docosahexaenoic acid promotes neurite growth in hippocampal neurons. J. Neurochem. 90, 979-988. doi:10.1111/j.1471-4159.2004.02520.x

Calon F, Lim GP, Yang F, Morihara T, Teter B, Ubeda O. 2004. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer`s disease mouse model. Neuron 43, 47-55. doi:10.1016/j.neuron.2004.08.013

Chen SG, Murakami K. 1994. Effects of cis-fatty acid on protein kinase C activation and protein phosphorilation in the hippocampus. J. Pharm. Sci. Technol. 48, 71-75.

Cole GM, Lim GP, Yang F, Teter B, Begum A, Ma Q, Harris-White M E, Frautschy S A. 2005. Prevention of Alzheimer’s disease: omega-3 fatty acid and phenolic anti-oxidant interventions. Neurobiol. Aging 26S, S133-S136. doi:10.1016/j.neurobiolaging.2005.09.005

Coleman P D, Yao PJ. 2003. Synaptic slaughter in Alzheimer’s disease. Neurobiol. Aging 24, 1023- 1027. doi:10.1016/j.neurobiolaging.2003.09.001

Connor WE, Neuringer M, Reisbick S. 1992. Essential fatty acids; the importance of n-3 fatty acids in the retina and brain. Nutr. Rev. 50, 21-29.

Connor WE, Connor JL. 2007. The importance of fish and docosahexaenoic acid in Alzheimer’s disease. Am. J. Clin. Nutr. 85, 929-930.

Evans J, Heron J, Francomb H, Oke S, Golding J. 2001. Cohort study of depressed mood during pregnancy and after childbirth. Brit. Med. J. 323, 257-260. doi:10.1136/bmj.323.7307.257

Feller S E, Gawrisch K, MacKerell AD. 2002. Polyunsaturated fatty acids in lipid bilayers: intrinsic and environmental contributions to their unique physical properties. J. Am. Chem. Soc. 124, 318-326. doi:10.1021/ja0118340

Fenton WS, Hibbeln J, Knable M. 2000. Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia. Biol. Psychiatry 47, 8-21. doi:10.1016/S0006-3223(99)00092-X

Fliesler SJ, Anderson RE. 1983. Chemistry and metabolism of lipids in the vertebrate retina. Prog. Lipid Res. 22, 79-131. doi:10.1016/0163-7827(83)90004-8

Frasure-Smith N, Lespérance F, Julien P. 2004. Major depression is associated with lower omega-3 fatty acid levels in patients with recent acute coronary syndromes. Biol. Psychiatry 55, 891-896. doi:10.1016/j.biopsych.2004.01.021

Freeman MP, Hibblen J, Wisner K, Watchman M, Gelenberg AJ. 2006. An open trial of omega-3 fatty acids for depression in pregnancy. Acta Neuropsychiatr. 18, 21-24. doi:10.1111/j.0924-2708.2006.00113.x

Freman M, Hibbblen J, Wisner K, Davis J, Mischoulon D, Peet M, Keck P, Marangell L, Richardson A, Lake J, Stoll A. 2006. Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J. Clin. Psychiatry 67, 1954-1967.

Gerbi A, Maixent JM, Barbey O, Jamme I, Pierlovisi M. 1998. Alterations of Na, K-ATPase isoenzymes in the rat diabetic neuropathy: protective effect of dietary supplementation with n-3 fatty acids. J. Neurochem. 71, 732-740.

Green KN, Martínez-Coria H, Khashwji H-, Hall E, Yurko- Mauro K, Ellis L, LaFerla F. 2007. Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-and tau pathology via a mechanism involving presenilin 1 levels. J. Neuroscien. 27, 4385-4395. doi:10.1523/JNEUROSCI.0055-07.2007

Haag M. 2003. Essential fatty acids and the brain. Can. J. Psychiatry. 48, 195-203.

Hashimoto M, Hossain S, Agdul H, Shido O. 2005. Docosahexaenoic acid-induced amelioration on impairment of memory learning in amiloid -infused rats relates to the decreases of amyloid and cholesterol levels in detergent-insoluble membrane fractions. Biochim. Biophys. Acta 1738, 91-98.

Hibbeln JR, Salem N. 1995. Dietary polyunsaturated fats and depression: when cholesterol alone doesn’t satisfy. Am. J. Clin. Nutr. 62, 1-9.

Hirashima F, Parow AM, Stoll AL, Demopulos CM, Damico KE, Rohan ML, Espesen JG, Zuo CS, Cohen BM, Renshaw PF. 2004. Omega-3 fatty acid treatment and T2 whole brain relaxation time in bipolar disorder. Am. J. Psychiatry 161, 1922-1924. doi:10.1176/appi.ajp.161.10.1922

Holman RT. 1998. The slow discovery of the importance of w-3 essential fatty acids in human health. J. Nutr. 128, 427S-433S.

Holub BJ. 1978. Differential utilization of 1-palmitoyl and 1-stearoyl homologues of various unsaturated 1,2- diacyl-sn-glycerols for phosphatidylcholine and phosphatidylethanolamine synthesis in rat liver microsomes. J. Biol. Chem. 253, 691-696.

Hong S, Gronert K, Devchand P, Moussignac RL, Serhan C. 2003. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain,human blood, and glial cells. J. Biol. Chem. 278, 14677-14687. doi:10.1074/jbc.M300218200

Horrobin DF, Glen AI, Vaddadi K. 1994. The membrane hypothesis of schizophrenia. Schizophr. Res. 13, 195- 207. doi:10.1016/0920-9964(94)90043-4

Hulbert AJ. 2003. Life, death and membrane bilayers. J. Exp. Biol. 206, 2303-2311. doi:10.1242/jeb.00399

Ikemoto A, Kobayashi T, Watanabe S, Okuyama H. 1997. Membrane fatty acid modifications of PC12 cells by arachidonate or docosahexaenoate affect neurite outgrowth but not norepinephrine release. Neurochem. Res. 22, 671-678. doi:10.1023/A:1027393724676

Jeffrey B, Weisinger H, Neuronger M, Mitchell B. 2001. The role of docosahexaenoic acid in retinal function. Lipids 36, 859-871. doi:10.1007/s11745-001-0796-3

Kale A, Joshi S, Naphade N, Sapkale S, Raju M, Pillai A, Nasrallah H, Mahadik S. 2008. Opposite changes in predominantly docosahexaenoic acid (DHA) in cerebrospinal fluid and red blood cells from nevermedicated first-episode psychotic patients. Schizophr. Res. 98, 295-301. doi:10.1016/j.schres.2007.09.036

Kang JX. 2005. Balance of omega-6/omega-3 essential fatty acids is important for health. World Rev. Nutr. Diet 95, 93-102. doi:10.1159/000088276

Kim HY, Akbar M, Lau A, Edsall L. 2000. Inhibition of neuronal apoptosis by docosahexaenoic acid. J. Biol. Chem. 45, 35215-35223. doi:10.1074/jbc.M004446200

Kim HY, Hamilton J. 2000. Accumulation of docosahexaenoic acid in phosphatidylserine is selectively inhibited by chronic ethanol exposure in C- 6 glioma cells. Lipids 3, 187-195. doi:10.1007/BF02664769

Kim HY, Bigelow J, Kevala JH. 2004. Substrate preference in phosphatidylserine biosynthesis for docosahexaenoic acid containing species. Biochemistry 3, 1030-1036. doi:10.1021/bi035197x

Kishida E, Yano M, Kasahara M, Masuzawa Y. 1998. Distinctive inhibitory activity of docosahexaenoic acid against sphingosine-induced apoptosis. Biochim. Biophys. Acta 1391, 401-408.

Kitajka K, Puskás L, Zvara A, Hackler L, Barceló-Coblijn G-, Yeo Y, Farkas T. 2002. The role of n-3 polyunsaturated fatty acids in brain: Modulation of brain gene expression by dietary n-3 fatty acids. Proc. Natl. Acad. Sci. 99, 2619-2624. doi:10.1073/pnas.042698699

Kin PY, Su KP. 2007. A meta-analytic review of doubleblind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J. Clin. Psychiatry 68, 1056-1061.

Lengqvist J., Mata de Urquiza A, Bergman AC, Willson TM, Sjovall J. 2004. Polyunsaturated fatty acids including docosahexaenoic acid and arachidonic acid bind to retinoid X receptor alpha ligand-binding domain. Mol. Cell. Proteomics 3, 692-703. doi:10.1074/mcp.M400003-MCP200

Lin PY, Su KP. 2007. A meta-analytic review of double blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J. Clin. Psychiatry 68, 1056-1061.

Locke CA, Stoll AL. 2001. Omega-3 fatty acids in major depression.World Rev. Nutr. Diet 89, 173-185. doi:10.1159/000059784

Logan AC. 2003. Neurobehavioural aspects of omega-3 fatty acids: possible mechanism and therapeutic value in major depression. Altern. Med. Rev. 8, 410-425.

Logan AC. 2004. Omega-3 fatty acids and major depression: a primer for the mental health professional. Lipids Health Dis. 3, 25-31. doi:10.1186/1476-511X-3-25

Lukiw W, Ciu J-G, Marcheselli V, Bodker M, Botkjaer A, Gotlinger K, Serhan C, Bazan N. 2005. A role of docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J. Clin. Invest. 115, 2774-2783. doi:10.1172/JCI25420

Lukiw W, Bazan N. 2006. Survival signalling in Alzheimer’s disease. Biochem. Soc. Trans. 34, 1277-1282. doi:10.1042/BST0341277

Mamalakis G, Tornaritis M, Kafatos A. 2002. Depression and adipose essential polyunsaturated fatty acids. Prostaglandins Leukot. Essent. Fatty Acids. 67, 311- 318. doi:10.1054/plef.2002.0435

Marszalek JR, Kitidis C, Dirusso CC, Lodish HF. 2005. Long-chain acyl CoA synthetase 6 preferentially promotes DHA metabolism. J. Biol. Chem. 20, 10817- 10826. doi:10.1074/jbc.M411750200

Martin RE, Bazan NG. 1992. Changing fatty acids content of growth cone lipids prior to synaptogenesis. J. Neurochem. 59, 318-325. doi:10.1111/j.1471-4159.1992.tb08906.x

Mata de Urquiza A, Liu S, Sjoberg M, Zetterstrom R, Griffiths W, Sjovall J, Perlman T. 2000. Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 290, 2140- 2144. doi:10.1126/science.290.5499.2140

McCann J, Ames B. 2005. Is docosahexaenoic acid, an n- 3 long chain polyunsaturated fatty acid, required for development of normal brain function? An overview of evidence from cognitive and behavioral test in humans and animals. Am. J. Clin. Nutr. 82, 281-295.

Meltzer HY. 1990. Role of serotonin in depression. Ann. N.Y. Acad. Sci. 600, 486-499. doi:10.1111/j.1749-6632.1990.tb16904.x

Moriguchi K, Yuri T, Yoshizawa K, Kiuchi K, Takada H. 2003. Dietary docosahexaenoic acid protects against–methyl-N-nitrosourea-induced retinal degeneration in rats. Exp. Eye Res. 77, 67-173. doi:10.1016/S0014-4835(03)00114-3

Nagata S. 1997. Apoptosis by death factor. Cell 88, 355-365. doi:10.1016/S0092-8674(00)81874-7

Nichizuka Y. 1995. Protein kinase C and lipid signalling for sustained cellular responses. FASEB J. 9, 484-496.

Narayanan BA, Narayanan K, Eddy BS. 2001. Docosahexaenoic acid regulated genes and transcription factors inducing apoptosis in human colon cancer cells. Int. J. Oncol. 9, 1255-1262.

Niu SL, Mitchell, DC, Lim SY, Wen ZM, Kim HY. 2004. Reduced G protein-coupled signalling efficiency in retinal rod outer segments in response to n-3 fatty acids deficiency. J. Biol. Chem. 279, 1098-1104. doi:10.1074/jbc.M404376200

Mozzi R, Buratta S, Goracci G. 2003. Metabolism and function of phosphatidylserine in mammalian brain. Neurochem. Res. 28, 195-214. doi:10.1023/A:1022412831330

Peet M, Murphy B, Shay J, Horrobin DF. 1998. Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients. Biol. Psychiatry 43, 315-319. doi:10.1016/S0006-3223(97)00206-0

Prasad MR, Lowell MA, Yatin M, Dhillon H, Markesbery WR. 1998. Regional membrane phospholipids alteration in Alzheimer’s disease. Neurochem. Res.23, 81-88. doi:10.1023/A:1022457605436

Puskas LG, Kitajka K, Nyakas C, Barcelo-Coblijn G, Farkas T. 2003. Short-term administration of omega-3 fatty acids from fish oil results in increased transthyretin transcription in old rat hippocampus. Proc. Natl. Cad. Sci. USA. 100, 1580-1585. doi:10.1073/pnas.0337683100

Rapoport SI. 2001. In vivo fatty acid incorporation into brain phospholipids in relation to plasma availability, signal transduction and membrane remodelling. J. Mol. Neurosci. 16, 243-261. doi:10.1385/JMN:16:2-3:243

Rojas CV, Martinez JI, Hoffman DR, Uauy R. 2003. Gene expression analysis in human fetal retinal explants treated with docosahexaenoic acid. Invest. Ophtalmol. Vis. Sci. 4, 3170-3177. doi:10.1167/iovs.02-1138

Rotstein NP, Aveldaño MI, Barrantes FJ, Roccamo AM, Politi LE. 1997. Apoptosis of retinal photoreceptors during development in vitro: protective effect of docosahexaenoic acid. J. Neurochem. 69, 504-513.

Salem N, Litman B, Kim HY. 2001. Mechanism of action of docosahexaenoic acid in the nervous system. Lipids 36, 945-959. doi:10.1007/s11745-001-0805-6

Sampath H, Ntambi JM. 2004. Polyunsaturated fatty acid regulation of gene expression. Nutr. Rev. 62, 333-339. doi:10.1111/j.1753-4887.2004.tb00058.x

Sastry PS, Rao KS. 2000. Apoptosis and the nervous system. J. Neurochem. 74, 1-20. doi:10.1046/j.1471-4159.2000.0740001.x

Serhan C, Chiang N. 2004. Novel endogenous small molecules as the checkpoint controllers in inflammation and resolution. Rheum. Dis. Clin. North. Am. 30, 69-95. doi:10.1016/S0889-857X(03)00117-0

Seung Kim HF, Weeber EJ, Sweatt JD, Stoll AL, Marangell LB. 2001. Inhibitory effects of omega-3 fatty acid on protein kinase C activity in vitro. Mol. Psychiatry 6, 246-248. doi:10.1038/

Simopoulos AP. 2002. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed. Pharmacother 56, 365-379. doi:10.1016/S0753-3322(02)00253-6

Soderberg M, Edlund C, Kristensson K, Dallner F. 1991. Fatty acid composition of brain phospholipids in aging and in Alzheimer’s disease. Lipids 26, 421-425. doi:10.1007/BF02536067

Stahl LA, Begg DP, Weisinger RS, Sinclair AJ. 2008. The role of omega-3 fatty acids in mood disorders. Curr. Opin. Invest. Drugs 9, 57-64.

Teague WE, Fuller NL, Rand RP, Gawrisch K. 2002. Polyunsaturated lipids in membrane fusion events. Cell. Mol. Biol. Lett. 7, 262-264.

Uauy R, Valenzuela A. 2000. Marine oils: the health benefits of n-3 fatty acids. Nutrition 16, 680-684. doi:10.1016/S0899-9007(00)00326-9

Valentine RC, Valentine DL. 2004. Omega-3 fatty acids in cellular membranes: a unified concept. Prog. Lipid Res. 43, 383-402. doi:10.1016/j.plipres.2004.05.004

Valenzuela A, Nieto S, Sanhueza J, Maymi P, Rojas I, Zañartu P. 2008. Supplementation of female rats with DHA-lysophosphatidylcholine increases DHA and acetylcholine content of the brain and improves the memory and learning capabilities of the pups. To be submitted. Valenzuela A, Sanhueza J, Nieto S. 2006. Docosahexaenoic acid (DHA), essentiality and requirements: why and how to provide supplementation. Grasas y Aceites 57, 229-237. doi:10.3989/gya.2006.v57.i2.43

Wadhwa PD, Sandman CA, Porto M, Dunkel-Schetter C, Garite TJ. 1993. The association between prenatal stress and infant birth weight and gestational age at birth: a prospective investigation. Am. J. Obstet. Gynecol. 169, 858-865.

Wainwright P. 2002. Dietary essential fatty acids and brain function: a developmental perspective on mechanism. Proc. Nutr. Soc. 61, 61-69. doi:10.1079/PNS2001130

Yao JK, Leonard S, Reddy R D. 2000. Membrane phospholipid abnormalities in post-mortem brains from schizophrenic patiens. Schizophr. Res. 42, 7-17. doi:10.1016/S0920-9964(99)00095-X

Yehuda S, Rabinovits S, Carasso R L, Mostofsky DI. 1998. Fatty acids and brain peptides. Peptides 19, 407-419. doi:10.1016/S0196-9781(97)00295-7




How to Cite

Valenzuela B A. Docosahexaenoic acid (DHA), an essential fatty acid for the proper functioning of neuronal cells: their role in mood disorders. Grasas aceites [Internet]. 2009Jun.30 [cited 2024May23];60(2):203-12. Available from: