Brain astrocyte synthesis of docosahexaenoic acid from n-3 fatty acids is limited at the elongation of docosapentaenoic acid

The phospholipids, particularly phosphatidylethanolamine, of brain gray matter are enriched with docosahexaenoic acid (22:6n-3). The importance of uptake of preformed 22:6n-3 from plasma compared with synthesis from the α-linolenic acid (18:3n-3) precursor in brain is not known. Deficiency of 18:3n-3 results in a compensatory increase in the n-6 docosapentaenoic acid (22:5n-6) in brain, which could be formed from the precursor linoleic acid (18:2n-6) in liver or brain. We studied n-3 and n-6 fatty acid incorporation in brain astrocytes cultured in chemically defined medium using delipidated serum supplemented with specific fatty acids. High performance liquid chromatography with evaporative light scattering detection and gas liquid chromatography were used to separate and quantify cell and media lipids and fatty acids. Although astrocytes are able to form 22:6n-3, incubation with 18:3n-3 or eicosapentaenoic acid (20:5n-3) resulted in a time and concentration dependent accumulation of 22:5n-3 and decrease in 22:6n-3 g/g cell fatty acids. Astrocytes cultured with 18:2n-6 failed to accumulate 22:5n-6.Astrocytes secreted cholesterol esters (CE) and phosphatidylethanolamine containing saturated and monounsaturated fatty acids, and arachidonic acid (20:4n-6) and 22:6n-3. These studies suggest conversion of 22:5n-3 limits 22:6n-3 synthesis, and show astrocytes release fatty acids in CE. The phospholipids, particularly phosphatidylethanolamine, of brain gray matter are enriched with docosahexaenoic acid (22:6n-3). The importance of uptake of preformed 22:6n-3 from plasma compared with synthesis from the α-linolenic acid (18:3n-3) precursor in brain is not known. Deficiency of 18:3n-3 results in a compensatory increase in the n-6 docosapentaenoic acid (22:5n-6) in brain, which could be formed from the precursor linoleic acid (18:2n-6) in liver or brain. We studied n-3 and n-6 fatty acid incorporation in brain astrocytes cultured in chemically defined medium using delipidated serum supplemented with specific fatty acids. High performance liquid chromatography with evaporative light scattering detection and gas liquid chromatography were used to separate and quantify cell and media lipids and fatty acids. Although astrocytes are able to form 22:6n-3, incubation with 18:3n-3 or eicosapentaenoic acid (20:5n-3) resulted in a time and concentration dependent accumulation of 22:5n-3 and decrease in 22:6n-3 g/g cell fatty acids. Astrocytes cultured with 18:2n-6 failed to accumulate 22:5n-6. Astrocytes secreted cholesterol esters (CE) and phosphatidylethanolamine containing saturated and monounsaturated fatty acids, and arachidonic acid (20:4n-6) and 22:6n-3. These studies suggest conversion of 22:5n-3 limits 22:6n-3 synthesis, and show astrocytes release fatty acids in CE. Brain gray matter is highly enriched in the long chain polyunsaturated fatty acids docosahexaenoic acid (22:6n-3) and arachidonic acid (20:4n-6) (1Sastry P.S. Lipids of nervous tissue: composition and metabolism.Prog. Lipid Res. 1985; 24: 169-176Google Scholar). Docosahexaenoic acid is formed from 18:3n-3 by Δ6 and Δ5 desaturation and elongation which gives rise to 20:5n-3 and 22:5n-3 in endoplasmic reticulum; 22:5n-3 is then elongated to 24:5n-3 and undergoes a second Δ6 desaturation to 24:6n-3 and is translocated to the peroxisomes where it undergoes one cycle of β-oxidation to form 22:6n-3 (Fig. 1)(2Luthria D.L. Mohammed B.S. Sprecher H. Regulation of the biosynthesis of 4,7,10,13,16,19-docosahexaenoic acid.J. Biol. Chem. 1996; 271: 16020-16025Google Scholar, 3Sprecher H. Luthria D.L. Mohammed B.S. Baykousheva S.P. Reevaluation of the pathways for biosynthesis of polyunsaturated fatty acids.J. Lipid Res. 1995; 36: 2471-2477Google Scholar, 4Voss A. Reinhard M. Sankarappa S. Sprecher H. The metabolism of 7,10,13,16,19-docosapentaenoic acid to 4,7,10,13, 16,19-docosahexaenoic acid in rat liver is independent of a 4-desaturase.J. Biol. Chem. 1991; 266: 19995-20000Google Scholar). Whether the Δ6 desaturase responsible for the desaturation of 18:3n-3 and 24:5n-3 are the same or different enzymes, and the steps involved in the intracellular movement of 24:6n-3 are not completely understood (5Innis S.M. Sprecher H. Hachey D. Anderson R. Edmond J. Neonatal polyunsaturated fatty acid metabolism.Lipids. 1999; 34: 139-149Google Scholar, 6Sprecher H. Chen Q. Yin F.Q. Regulation of the biosynthesis of 22:5n-6 and 22:6n-3: a complex intracellular process.Lipids. 1999; 34: S153-S156Google Scholar). Synthesis of 20:4n-6 from 18:2n-6 is believed to involve the same Δ6 and Δ5 desaturases involved in the metabolism of 18:3n-3. Further metabolism of 20:4n-6 leads to formation of 22:5n-6 in an analogous pathway to that used for formation of 22:6n-3 (6Sprecher H. Chen Q. Yin F.Q. Regulation of the biosynthesis of 22:5n-6 and 22:6n-3: a complex intracellular process.Lipids. 1999; 34: S153-S156Google Scholar). Dietary deficiency of 18:3n-3 results in a characteristic increase in 22:5n-6 in brain phospholipids, such that the total amount of carbon chain n-6 plus n-3 fatty acids is maintained (7Galli C. Trzeciak H.I. Paoletti R. Effects of dietary fatty acids on the fatty acid composition of brain ethanolamine phosphoglyceride: reciprocal replacement of n-6 and n-3 polyunsaturated fatty acids.Biochem. Biophys. Acta. 1971; 248: 449-454Google Scholar, 8Hrboticky N. MacKinnon M.J. Innis S.M. Effect of a vegetable oil formula rich in linioleic acid on tissue fatty acid accretion in the brain, liver, plasma, and erythrocytes of infant piglets.Am. J. Clin. Nutr. 1990; 51: 173-182Google Scholar, 9Innis S.M. Essential fatty acids in growth and development. Prog.J. Lipid Res. 1991; 30: 39-103Google Scholar, 10Neuringer M. Connor W.E. Lin D.S. Barstad L. Luck S. Biochemical and functional effects of prenatal and postnatal ω-3 deficiency on retina and brain in rhesus monkeys.Proc. Natl. Acad. Sci. USA. 1986; 83: 4021-4025Google Scholar). Despite this, decreased 22:6n-3 in the developing brain and retina results in decreased visual and neural function, and altered monoaminergic neurotransmitter metabolism (9Innis S.M. Essential fatty acids in growth and development. Prog.J. Lipid Res. 1991; 30: 39-103Google Scholar, 10Neuringer M. Connor W.E. Lin D.S. Barstad L. Luck S. Biochemical and functional effects of prenatal and postnatal ω-3 deficiency on retina and brain in rhesus monkeys.Proc. Natl. Acad. Sci. USA. 1986; 83: 4021-4025Google Scholar, 11Bourre J.M. Francois M. Youyou A. Dumont O. Piciotti M. Pascal G. Durand G. The effects of dietary α-linolenic acid on the composition of nerve membranes, enzymatic activity, amplitude of electrophysiological parameters, resistance to poisons and performance of learning tasks in rats.J. Nutr. 1989; 119: 1880-1892Google Scholar, 12De la Presa Owens S. Innis S.M. Docosahexaenoic and arachidonic acid reverse changes in dopaminergic and sertoninergic neurotransmitters in piglet frontal cortex caused by a linoleic and alpha linolenic acid deficient diet.J. Nutr. 1999; 129: 2088-2093Google Scholar, 13Delion S. Chalon S. Herault J. Guilloteau D. Besnard J.C. Durand G. Chronic dietary α-linoleic acid deficiency alters dopaminergic and serotinergic neurotransmitters in rats.J. Nutr. 1994; 124: 2466-2476Abstract Full Text PDF Scopus (281) Google Scholar). Uptake and conversion of 14C-labeled 18:3n-3 to n-3 products by brain and isolated brain cells has been shown (14Dhopesharkar G.A. Subramanian C. Biosynthesis of polyunsaturated fatty acids in the developing brain: I. Metabolic transformation of intracranially administered 1–14C linolenic acid.Lipids. 1976; 11: 67-71Google Scholar, 15Moore S.A. Yoder E. Murphy S. Dutton G.R. Spector A.A. Astrocytes, not neurons, produce docosahexaenoic acid (22:6n-3) and arachidonic acid (20:4n-6).J. Neurochem. 1991; 56: 518-524Google Scholar, 16Bernoud N. Fenart L. Benistant C. Pageaux J.F. Dehouck M.P. Moliere P. Lagarde M. Cecchelli R. Lecerf J. Astrocytes are mainly responsible for the polyunsaturated fatty acid enrichment in blood-brain barrier endothelial cells in vitro.J. Lipid Res. 1998; 39: 1816-1824Google Scholar). However, developing brain is also able to take up 22:6n-3 and 20:4n-6 from plasma (12De la Presa Owens S. Innis S.M. Docosahexaenoic and arachidonic acid reverse changes in dopaminergic and sertoninergic neurotransmitters in piglet frontal cortex caused by a linoleic and alpha linolenic acid deficient diet.J. Nutr. 1999; 129: 2088-2093Google Scholar, 17Rapoport S.I. Chang M.C.J. Spector A.A. Delivery and turnover of plasma-derived essential PUFAs in mammalian brain.J. Lipid Res. 2001; 42: 678-685Google Scholar, 18Su H.M. Bernardo L. Mirmiran M. Ma X.H. Corso T.N. Nathanielsz P.W. Brenna J.T. Bioequivalence of dietary α-linolenate and docosahexaenoate acids as possible sources of docosahexaenoate accretion in brain and associated organs of neonatal baboons.Ped. Res. 1999; 45: 87-93Google Scholar). The importance of uptake of 22:6n-3 from plasma compared with synthesis of 22:6n-3 in the brain following uptake of n-3 fatty acid precursors is not known (5Innis S.M. Sprecher H. Hachey D. Anderson R. Edmond J. Neonatal polyunsaturated fatty acid metabolism.Lipids. 1999; 34: 139-149Google Scholar). However, studies with preterm infants have shown that the dietary intake and blood lipid level of 22:6n-3 is positively related to visual and neural development (19Birch E.E. Hoffman D.R. Uauy R. Birch D.G. Prestidge C. Visual acuity and the essentility of docosahexaenoic acid and arachidonic acid in the diet of term infants.Pediatr Res. 1998; 44: 201-209Google Scholar, 20Carlson S.E. Werkman S.H. Rhodes P.G. Tolley E.A. Visual-acuity development in healthy preterm infants: effect of marine-oil supplementation.Am. J. Clin. Nutr. 1993; 58: 35-42Google Scholar, 21Innis S.M. Gilley J. Werker J. Are human-milk long-chain polyunsaturated fatty acids related to visual and neural development in breast-fed infants ?.Pediatrics. 2001; 139: 532-538Google Scholar, 22O'Connor D.L. Auestad N. Jacobs J. and development in preterm infants long-chain polyunsaturated fatty a 2001; Scholar). in studies using precursors have shown brain not neurons, are of 22:6n-3 and have that astrocytes be in 22:6n-3 to brain cells S.A. Yoder E. Murphy S. Dutton G.R. Spector A.A. Astrocytes, not neurons, produce docosahexaenoic acid (22:6n-3) and arachidonic acid (20:4n-6).J. Neurochem. 1991; 56: 518-524Google Scholar, 16Bernoud N. Fenart L. Benistant C. Pageaux J.F. Dehouck M.P. Moliere P. Lagarde M. Cecchelli R. Lecerf J. Astrocytes are mainly responsible for the polyunsaturated fatty acid enrichment in blood-brain barrier endothelial cells in vitro.J. Lipid Res. 1998; 39: 1816-1824Google Scholar). the of n-3 fatty acid metabolism in the brain by that the elongation of 22:5n-3 limits the formation of 22:6n-3 from n-3 fatty acid precursors in neonatal brain We also show that astrocytes to accumulate 22:5n-6 cultured in the of 18:2n-6 18:3n-3. serum and n-6 and n-3 fatty acids, used chemically defined media with delipidated serum or supplemented with specific fatty acids. of performance liquid chromatography with evaporative light scattering detection also show that brain astrocytes cholesterol esters (CE) and phosphatidylethanolamine suggest that and Δ6 desaturation of 24:6n-3 and limits the formation of 22:6n-3 and 22:5n-6 in brain and suggest astrocytes an in fatty acids to cells in CE. acids were from and and from and fatty acid were from serum and were from were from gray matter of rat using the of and J. of separate and cell from rat Biol. Scholar). The enriched in containing and a of in tissue and maintained in supplemented with and The media and to the of and were by the of which form a of were and by J. of separate and cell from rat Biol. Scholar). The astrocytes formed a and were astrocytes by and light as by E. L. of brain specific in term cultured rat cells and in rat Neurochem. Scholar). Astrocytes from neonatal rat brain, and changes to in with S. R. L. of astrocytes in of Clin. Biol. Res. Scholar). to of of to the astrocytes from a to a to that in rat astrocytes S. R. L. of astrocytes in of Clin. Biol. Res. Scholar). Whether and changes changes in n-6 and n-3 fatty acid uptake is not known. compared n-3 and n-6 fatty acid uptake and incorporation in neonatal astrocytes and in astrocytes with and concentration studies with 18:3n-3 supplemented media in the accumulation of n-3 fatty acids neonatal astrocytes and astrocytes with We that cell of neural are known to to and fatty acids of the of essential fatty acid metabolism by fatty acids in cultured and Biophys. Acta. Scholar, E. fatty acid metabolism in cells in Neurochem. 24: and not development analogous to that in results for neonatal astrocytes with are The uptake and incorporation of n-3 and n-6 fatty acids lipids studied in tissue The cells were maintained in a in with delipidated with media to the of L. of serum for in cell 1976; and the of n-6 and n-3 fatty acid by gas liquid chromatography S.M. Gilley J. Werker J. Are human-milk long-chain polyunsaturated fatty acids related to visual and neural development in breast-fed infants ?.Pediatrics. 2001; 139: 532-538Google Scholar, Innis S.M. infant plasma n-6 and n-3 fatty acids are related to plasma fatty acids, of and and J. Clin. Nutr. Scholar). acids, as were with fatty acid serum a of a of cell were lipids were from the cells and media J. M. for the and of total lipids from Biol. Chem. the and the lipids in of and using a with an and The and the The a and We used a of in a with a of The to an and a detection and of the lipid with a of a of and the to the of the were using for lipid and were using the The of cholesterol in the media by acids were as esters using acid as the with a with a and a S.M. Gilley J. Werker J. Are human-milk long-chain polyunsaturated fatty acids related to visual and neural development in breast-fed infants ?.Pediatrics. 2001; 139: 532-538Google Scholar, Innis S.M. infant plasma n-6 and n-3 fatty acids are related to plasma fatty acids, of and and J. Clin. Nutr. Scholar). Although brain astrocytes as as are enriched in 22:6n-3 J.M. A. Dumont O. A. C. J. A. Effect of polyunsaturated fatty acids on brain cells in in a chemically defined Neurochem. fatty acid be by uptake and desaturation and elongation of 18:3n-3 or or by uptake of 22:6n-3 from Astrocytes cultured in defined media with delipidated serum with and 18:3n-3 of 22:6n-3 in and (Fig. is characteristic of brain gray matter (1Sastry P.S. Lipids of nervous tissue: composition and metabolism.Prog. Lipid Res. 1985; 24: 169-176Google 22:6n-3 enriched in cultured neonatal cells with resulted in accumulation of 22:5n-3 in lipid such that 22:5n-3 the n-3 fatty acid in and The of 18:3n-3 the cell lipids of astrocytes cultured with 18:3n-3 22:5n-3 (Fig. of the 18:3n-3 resulted in incorporation of accumulation of carbon chain n-3 fatty acids total cell fatty of n-3 fatty acids in cell lipids of neonatal astrocytes cultured with delipidated serum with or 18:3n-3 for or The cell lipids were and by as in and The are and from a of separate not in the with the in 22:6n-3 formation the level of elongation of 22:5n-3 to 24:5n-3 by a second Δ6 the n-3 fatty acid in astrocytes cultured with 20:5n-3 22:5n-3 (Fig. Astrocytes up and 22:6n-3 from the media by a increase in the 20:5n-3 and 22:5n-3 compared with cells cultured 22:6n-3, chain and of 22:6n-3. Astrocytes cultured in n-3 fatty acid deficient media with 18:2n-6 not accumulate 22:5n-6 for reciprocal replacement of 22:6n-3 (Fig. astrocytes cultured with 18:2n-6 20:4n-6 and not of n-3 fatty acids in cell lipids of isolated neonatal astrocytes and astrocytes cultured with delipidated serum or with 18:2n-6 and n-3 fatty acids. The cell lipids were and by as in and The are and from a of separate not in the in the of serum of the lipids secreted by the by development of lipid with with which and of lipid on chromatography and or enzymatic of the media is from the enrichment of in the media compared with the astrocytes in which phosphatidylethanolamine, and cholesterol were the lipids (Fig. secreted the media in fatty with of 20:4n-6 and 22:6n-3 18:3n-3 not secreted in cholesterol esters in astrocytes cultured with fatty However, astrocytes cultured with 18:3n-3 22:6n-3 in CE. The neonatal brain of 22:6n-3 in the the of which in the rat The accumulation of and docosahexaenoate in the developing rat brain.J. Neurochem. Scholar). 22:6n-3 in brain phospholipids, to dietary results in a reciprocal increase in 22:5n-6 in brain (7Galli C. Trzeciak H.I. Paoletti R. Effects of dietary fatty acids on the fatty acid composition of brain ethanolamine phosphoglyceride: reciprocal replacement of n-6 and n-3 polyunsaturated fatty acids.Biochem. Biophys. Acta. 1971; 248: 449-454Google Scholar, 8Hrboticky N. MacKinnon M.J. Innis S.M. Effect of a vegetable oil formula rich in linioleic acid on tissue fatty acid accretion in the brain, liver, plasma, and erythrocytes of infant piglets.Am. J. Clin. Nutr. 1990; 51: 173-182Google Scholar, 9Innis S.M. Essential fatty acids in growth and development. Prog.J. Lipid Res. 1991; 30: 39-103Google Scholar, 10Neuringer M. Connor W.E. Lin D.S. Barstad L. Luck S. Biochemical and functional effects of prenatal and postnatal ω-3 deficiency on retina and brain in rhesus monkeys.Proc. Natl. Acad. Sci. USA. 1986; 83: 4021-4025Google Scholar). The results of studies show that the of 18:3n-3 and 20:5n-3 astrocytes from rat brain is in n-3 fatty acid deficient media with 18:2n-6 resulted in accumulation of 20:4n-6 and not 22:5n-6. The pathway for synthesis of 22:6n-3 from 18:3n-3 Δ6 desaturation and elongation and Δ5 desaturation to by elongation to 22:5n-3 then to and a second Δ6 desaturation to 24:6n-3 (Fig. The 24:6n-3 is then to the peroxisomes and to 22:6n-3 one cycle of β-oxidation D.L. Mohammed B.S. Sprecher H. Regulation of the biosynthesis of 4,7,10,13,16,19-docosahexaenoic acid.J. Biol. Chem. 1996; 271: 16020-16025Google Scholar, 3Sprecher H. Luthria D.L. Mohammed B.S. Baykousheva S.P. Reevaluation of the pathways for biosynthesis of polyunsaturated fatty acids.J. Lipid Res. 1995; 36: 2471-2477Google Scholar, 4Voss A. Reinhard M. Sankarappa S. Sprecher H. The metabolism of 7,10,13,16,19-docosapentaenoic acid to 4,7,10,13, 16,19-docosahexaenoic acid in rat liver is independent of a 4-desaturase.J. Biol. Chem. 1991; 266: 19995-20000Google Scholar). Synthesis of 22:5n-6 from 18:2n-6 an analogous pathway (6Sprecher H. Chen Q. Yin F.Q. Regulation of the biosynthesis of 22:5n-6 and 22:6n-3: a complex intracellular process.Lipids. 1999; 34: S153-S156Google Scholar). of lipids from cells cultured with 18:3n-3 or 18:2n-6 of accumulation of n-3 or n-6 fatty acids, of 22:5n-3 or in the of and 22:5n-3 are in neural cells in (1Sastry P.S. Lipids of nervous tissue: composition and metabolism.Prog. Lipid Res. 1985; 24: 169-176Google Scholar). results suggest that the in the metabolism of n-3 fatty acid precursors to 22:6n-3 is the level of elongation to the and the Δ6 not the steps of 18:3n-3 it is possible that the elongation of fatty acids is with the for Δ6 desaturation and chain the desaturation of 18:3n-3 and 24:5n-3 involve the same Δ6 desaturase 18:3n-3 could metabolism of The accumulation of 22:5n-3 in astrocytes cultured with and that metabolism of n-3 fatty acids is by the metabolism of studies have of 22:6n-3 synthesis in brain and brain astrocytes on the of from in 22:6n-3 (14Dhopesharkar G.A. Subramanian C. Biosynthesis of polyunsaturated fatty acids in the developing brain: I. Metabolic transformation of intracranially administered 1–14C linolenic acid.Lipids. 1976; 11: 67-71Google Scholar, 15Moore S.A. Yoder E. Murphy S. Dutton G.R. Spector A.A. Astrocytes, not neurons, produce docosahexaenoic acid (22:6n-3) and arachidonic acid (20:4n-6).J. Neurochem. 1991; 56: 518-524Google Scholar, 16Bernoud N. Fenart L. Benistant C. Pageaux J.F. Dehouck M.P. Moliere P. Lagarde M. Cecchelli R. Lecerf J. Astrocytes are mainly responsible for the polyunsaturated fatty acid enrichment in blood-brain barrier endothelial cells in vitro.J. Lipid Res. 1998; 39: 1816-1824Google Scholar, M. S.A. Spector A.A. Docosahexaenoic acid synthesis from n-3 polyunsaturated fatty acids in rat brain Lipid Res. 2001; 42: Scholar). with have shown the in astrocytes cultured with is not 22:6n-3 M. S.A. Spector A.A. Docosahexaenoic acid synthesis from n-3 polyunsaturated fatty acids in rat brain Lipid Res. 2001; 42: not the for 22:6n-3 synthesis S.A. Yoder E. Murphy S. Dutton G.R. Spector A.A. Astrocytes, not neurons, produce docosahexaenoic acid (22:6n-3) and arachidonic acid (20:4n-6).J. Neurochem. 1991; 56: 518-524Google Scholar, 16Bernoud N. Fenart L. Benistant C. Pageaux J.F. Dehouck M.P. Moliere P. Lagarde M. Cecchelli R. Lecerf J. Astrocytes are mainly responsible for the polyunsaturated fatty acid enrichment in blood-brain barrier endothelial cells in vitro.J. Lipid Res. 1998; 39: 1816-1824Google Scholar). We suggest the synthesis of 22:6n-3 from n-3 or of 22:5n-6 from 18:2n-6 of n-3 fatty acid is not the which developing brain of 22:6n-3 or 22:5n-6. However, it is possible that of neonatal brain astrocytes a for metabolism of and which is in S.I. Chang M.C.J. Spector A.A. Delivery and turnover of plasma-derived essential PUFAs in mammalian brain.J. Lipid Res. 2001; 42: 678-685Google have that of rat brain 22:6n-3 is with 22:6n-3 from the plasma fatty acid of 22:6n-3 and and to be related to and J. and 1995; Scholar, I. for the of docosahexaenoic acid in the Res. Scholar, A. The of docosahexaenoic acid containing in visual 2001; Scholar, cells a in the of docosahexaenoic acid by cells and Res. 11: Scholar). These pathways are also to the functional of 22:6n-3 in neural and is to a of 22:6n-3 cells a in the of docosahexaenoic acid by cells and Res. 11: with the of the brain to 22:6n-3 dietary n-3 fatty acid deficiency J. Dietary and of alpha linolenic acid in Lipid Res. Scholar). accumulation of 22:6n-3, is essential to the lipid growth that brain development (9Innis S.M. Essential fatty acids in growth and development. Prog.J. Lipid Res. 1991; 30: 39-103Google and to is by visual and neural (9Innis S.M. Essential fatty acids in growth and development. Prog.J. Lipid Res. 1991; 30: 39-103Google Scholar, 10Neuringer M. Connor W.E. Lin D.S. Barstad L. Luck S. Biochemical and functional effects of prenatal and postnatal ω-3 deficiency on retina and brain in rhesus monkeys.Proc. Natl. Acad. Sci. USA. 1986; 83: 4021-4025Google Scholar, 11Bourre J.M. Francois M. Youyou A. Dumont O. Piciotti M. Pascal G. Durand G. The effects of dietary α-linolenic acid on the composition of nerve membranes, enzymatic activity, amplitude of electrophysiological parameters, resistance to poisons and performance of learning tasks in rats.J. Nutr. 1989; 119: 1880-1892Google Scholar, 12De la Presa Owens S. Innis S.M. Docosahexaenoic and arachidonic acid reverse changes in dopaminergic and sertoninergic neurotransmitters in piglet frontal cortex caused by a linoleic and alpha linolenic acid deficient diet.J. Nutr. 1999; 129: 2088-2093Google Scholar, 13Delion S. Chalon S. Herault J. Guilloteau D. Besnard J.C. Durand G. Chronic dietary α-linoleic acid deficiency alters dopaminergic and serotinergic neurotransmitters in rats.J. Nutr. 1994; 124: 2466-2476Abstract Full Text PDF Scopus (281) Google Scholar). an of the importance of the plasma of 22:6n-3 in neural of 22:6n-3 is in the of plasma 22:6n-3 in infants fatty acid (19Birch E.E. Hoffman D.R. Uauy R. Birch D.G. Prestidge C. Visual acuity and the essentility of docosahexaenoic acid and arachidonic acid in the diet of term infants.Pediatr Res. 1998; 44: 201-209Google Scholar, 20Carlson S.E. Werkman S.H. Rhodes P.G. Tolley E.A. Visual-acuity development in healthy preterm infants: effect of marine-oil supplementation.Am. J. Clin. Nutr. 1993; 58: 35-42Google Scholar, 21Innis S.M. Gilley J. Werker J. Are human-milk long-chain polyunsaturated fatty acids related to visual and neural development in breast-fed infants ?.Pediatrics. 2001; 139: 532-538Google Scholar, 22O'Connor D.L. Auestad N. Jacobs J. and development in preterm infants long-chain polyunsaturated fatty a 2001; and in acids in Nutr. 2001; Scholar). is that the liver is able to 18:3n-3 to 22:6n-3 H. Luthria D.L. Mohammed B.S. Baykousheva S.P. Reevaluation of the pathways for biosynthesis of polyunsaturated fatty acids.J. Lipid Res. 1995; 36: 2471-2477Google and studies have that plasma 22:6n-3, which could be from synthesis in liver or from the is up and brain lipids (12De la Presa Owens S. Innis S.M. Docosahexaenoic and arachidonic acid reverse changes in dopaminergic and sertoninergic neurotransmitters in piglet frontal cortex caused by a linoleic and alpha linolenic acid deficient diet.J. Nutr. 1999; 129: 2088-2093Google Scholar, 17Rapoport S.I. Chang M.C.J. Spector A.A. Delivery and turnover of plasma-derived essential PUFAs in mammalian brain.J. Lipid Res. 2001; 42: 678-685Google Scholar, 18Su H.M. Bernardo L. Mirmiran M. Ma X.H. Corso T.N. Nathanielsz P.W. Brenna J.T. Bioequivalence of dietary α-linolenate and docosahexaenoate acids as possible sources of docosahexaenoate accretion in brain and associated organs of neonatal baboons.Ped. Res. 1999; 45: 87-93Google Scholar, docosahexaenoate is to the developing brain and retina by the Natl. Acad. Sci. USA. 1989; Scholar). is also that the of the brain (12De la Presa Owens S. Innis S.M. Docosahexaenoic and arachidonic acid reverse changes in dopaminergic and sertoninergic neurotransmitters in piglet frontal cortex caused by a linoleic and alpha linolenic acid deficient diet.J. Nutr. 1999; 129: 2088-2093Google Scholar, 18Su H.M. Bernardo L. Mirmiran M. Ma X.H. Corso T.N. Nathanielsz P.W. Brenna J.T. Bioequivalence of dietary α-linolenate and docosahexaenoate acids as possible sources of docosahexaenoate accretion in brain and associated organs of neonatal baboons.Ped. Res. 1999; 45: 87-93Google and astrocytes in to take up 22:6n-3 (Fig. M. S.A. Spector A.A. Docosahexaenoic acid synthesis from n-3 polyunsaturated fatty acids in rat brain Lipid Res. 2001; 42: the with which 18:3n-3 be 22:6n-3 and The for chain and of 22:6n-3 to 22:5n-3 and 20:5n-3 in astrocytes cultured with 22:6n-3 that the for β-oxidation is not to 22:6n-3 The the that the of brain 22:6n-3 is the plasma, from the liver or Neonatal brain astrocytes cultured in the of serum secreted and of and fatty acids. is cholesterol and saturated and monounsaturated fatty acids are in the developing brain J. G. D. Dietary cholesterol and the of cholesterol in brain of developing rats.J. Nutr. 1991; Scholar, J. E.A. acid and for the developing brain.J. Neurochem. 1998; from in of 18:3n-3 for fatty acid and cholesterol synthesis in the brain J. G. D. Dietary cholesterol and the of cholesterol in brain of developing rats.J. Nutr. 1991; Scholar, Edmond J. The of acid in brain of the developing Scholar, Brenna J.T. is a pathway in neonatal metabolism of and 1999; Scholar, Q. 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