AP Bio Neurobiology of Lipid Metabolism in Autism Spectrum Disorders

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Neurosignals 2010;18:98112

DOI: 10.1159/000323189

The Neurobiology of Lipid Metabolism inAutism Spectrum Disorders

Javaneh Tamijib, c Dorota A. Crawfordac

aDepartment of Biology, bSchool of Kinesiology and Health Science, cNeuroscience Graduate Diploma Program,

York University, Toronto, Ont., Canada

volvement of lipid neurobiology in the pathology of neuro-

developmental disorders such as autism is compelling and

opens up an interesting possibility for further investigation

of this metabolic pathway. Copyright 2011 S. Karger AG, Basel

Introduction

Autistic disorder is a behaviorally defined neurode-velopmental disorder of childhood characterized by def-icits in social interaction, language, communication andrepetitive behaviors that manifest in early postnatal life[1]. It belongs to a spectrum of closely related conditionsalso referred to as autism spectrum disorders (ASDs)that also includes pervasive developmental disorder nototherwise specified, Aspergers syndrome, and child-

hood disintegrative disorder. The incidence of ASDs hasincreased significantly over the last decades and is cur-rently 1 in 150, affecting boys four times more often thangirls [2, 3]. A strong genetic component is indicated bythe high concordance rates in monozygotic twins (7095%) versus dizygotic twins (023%) [1, 46]. Many geneshave been implicated in the etiology of the disorder [4]in addition to the contributing environmental factors [7

Key Words

Autism Abnormal fatty acid metabolism Dietary

supplementation Genetic defects Arachidonic acid

Prostaglandins

Abstract

Autism is a neurodevelopmental disorder characterized by

impairments in communication and reciprocal social inter-

action, coupled with repetitive behavior, which typically

manifests by 3 years of age. Multiple genes and early expo-

sure to environmental factors are the etiological determi-

nants of the disorder that contribute to variable expression

of autism-related traits. Increasing evidence indicates that

altered fatty acid metabolic pathways may affect proper

function of the nervous system and contribute to autism

spectrum disorders. This review provides an overview of the

reported abnormalities associated with the synthesis ofmembrane fatty acids in individuals with autism as a result

of insufficient dietary supplementation or genetic defects.

Moreover, we discuss deficits associated with the release of

arachidonic acid from the membrane phospholipids and its

subsequent metabolism to bioactive prostaglandins via

phospholipase A2-cyclooxygenase biosynthetic pathway in

autism spectrum disorders. The existing evidence for the in-

Received: August 18, 2010

Accepted after revision: November 29, 2010

Published online: February 4, 2011

Dr. Dorota Anna CrawfordYork University, Faculty of Health4700 Keele Street, Bethune College, Room 346

Toronto, ON M3J 1P3 (Canada)Tel. +1 416 736 2100, ext. 21058, Fax +1 416 736 5774, E-Mail dakc @ yorku.ca

2011 S. Karger AG, Basel1424862X/10/01820098$26.00/0

Accessible online at:www.karger.com/nsg
http://dx.doi.org/10.1159%2F000323189http://dx.doi.org/10.1159%2F000323189


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Neurosignals 2010;18:98112 99

9], which together determine the broad severity of autismphenotype.

The emerging evidence implies that abnormal fatty acidmetabolism may play a contributing role in the pathology

of autism [1012]. Recent literature suggests that fatty acidhomeostasis may be altered in autism as a result of insuf-ficient dietary supplementation, genetic defects, functionof enzymes involved in their metabolism, or influence ofvarious environmental agents such as infections, inflam-mation or drugs. This review provides an overview of theproposed candidate sites along the lipid metabolic pathwaythat have been implicated in the pathology of ASDs.

Lipid Signaling in the Nervous System

Dry human brain, by weight, is composed of approx-imately 60% lipids with over 20% polyunsaturated fatty

acids (PUFAs) [1315]. PUFAs, predominantly arachi-donic acid (AA, 20: 4n-6), eicosapentaenoic acid (EPA,20: 5n-3) and docosahexaenoic acid (DHA, 22: 6n-3), aremajor components of the neural cell membrane phos-pholipids. AA and EPA/DHA are derived from two ma-

jor types of PUFAs, omega-6 linoleic acid (LA; 18: 2n-6)and omega-3-linolenic acid (ALA; 18: 3n-3), respective-ly [16, 17] (fig. 1). Proper content of omega-3 and ome-

LA ALA

AAEPA

DHA

PGG2

PLA2

COX-1, -2

PGH2

TxA2PGD2

PGE2

PGF2

FP receptor

PGI2

IP receptor

TP receptor

DP receptor

AA

Oxidative stress Lipid peroxidationAntioxidant capacity

FADS1/2FADS1/2

Wnt/BMP

TxB2

EP receptor

Misoprostol

Infections

Inflammation

iPF2-VI

Ca2+

6 3

6ketoPGF1

8isoPGF2

C

olorversiona

vailable

online

Fig. 1.Schematic diagram illustrating the most common abnormalities in bioactive lipid signaling pathwaysassociated with ASDs.


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Tamiji /CrawfordNeurosignals 2010;18:98112100

ga-6 fatty acids is important for the integrity and properfunctioning of the plasma membrane, such as modula-tion of ion channels, enzymes and receptor activity [18,19].

DHA and AA play an important role in the nervoussystem, including retinal development and vision [20, 21],

neurogenesis and neuronal differentiation [2224], neu-ral plasticity and signal transduction [25, 26], inflamma-tion [2730], and learning and memory [3133]. Thesefunctions may be regulated by a number of gene productsactivated by PUFAs during development [3439]. Theplasma membrane phospholipids serve as a supply of sec-ond messenger molecules important for normal func-tioning of the brain [40, 41]. PUFA such as AA or DHAcan also be released from membrane phospholipids bythe action of phospholipase A2(PLA2) and subsequentlymetabolized into various types of bioactive prostanoids(fig. 1). Cyclooxygenase-1 enzyme (COX-1), constitutive

form, or cyclooxygenase-2 (COX-2), inducible form, con-verts AA to the unstable PGG2intermediate and then tothe prostanoid precursor PGH2, which is further metab-olized by the prostaglandin (PG) or thromboxane syn-thases into the major lipid signaling messengers (eico-sanoids) such as PGs (PGE2, PGF2, PGD2, PGI2), andthromboxane A2 (TxA2). The five downstream pros-tanoids are important signaling molecules that exerttheir effects through activation of their respective G-pro-tein-coupled receptors called EP (E-prostanoid), FP, DP,IP, and TP receptors [4244]. The released prostanoidsplay important roles in normal neural function including

sleep induction (PGD2), spatial learning, synaptic plastic-ity and long-term potentiation or inflammation (PGE2)[13, 45]. Of these, PGE2has gained a considerable atten-tion recently for its involvement in activity-dependentsynaptic plasticity via four receptor subtypes EP1EP4[4648].

It is now evident that the brain proper function relieson a balance between the constant supply of the omega-3and -6 fatty acids in the blood from dietary PUFAs andthe release of their metabolites from membrane phospho-lipids via activation of PLA2and other key downstreamenzymes (fig. 1) [31, 35, 4952]. Therefore, alterations of

the fatty acids metabolic pathway may affect proper func-tion of the nervous system. An association between ASDsand abnormalities at various sites of the lipid metabolicpathway has been reported in various studies and is dis-cussed in the following sections.

Dietary Lipid Imbalances in ASDs

During the last trimester of pregnancy and the first 2years of life, human brain undergoes an immense growthduring which unesterified omega-3 and omega-6 fattyacid content of the grey and white matters increase con-

siderably [53, 54]. Because of the increased demand, suf-ficient supply of the essential PUFAs and proper ratio ofAA to DHA particularly during early life is critical forproper development and function of the nervous system[16, 31, 5559]. Both human and animal studies have cor-related the presence of AA and DHA during critical pe-riod of development to enhanced visual, cognitive andmotor functions [23, 6063]. A link between imbalancesin the AA to DHA composition and abnormalities of fat-ty acid metabolism have been shown to play a role in thepathology of various psychiatric disorders, including at-tention deficit hyperactivity disorder, dyslexia, dysprax-

ia, bipolar disorder and schizophrenia [51, 6471].Insufficient dietary intake of PUFA during early de-

velopment and abnormal lipid metabolism have beenshown to occur in ASDs as well. Current literature sug-gests that altered level of omega-6 fatty acids (i.e. AA) andomega-3 fatty acid (i.e. DHA) may result in an imbalancein the ratio between these PUFAs in the nervous systemand potentially contribute to the behavioral outcomesseen in autism. A survey study reported that childrenwho were not breastfed or fed on infant formula not sup-plemented with PUFAs were significantly more likely todevelop autism [72]. Altered level of LA, DHA and AA

and significantly higher AA:DHA ratio was reported inthe blood samples (plasma and red blood cells) of autismpatients compared to the control group [15]. Other stud-ies have reported a significant reduction in AA and DHAlevels in the plasma of autistic children compared to thelevels in controls [7375]. Decreased level of DHA andsubsequently higher AA:DHA ratio were also detected inthe red blood cells of children with regressive autism andAspergers syndrome compared to typically developingcontrols [14, 76]. Sliwinski et al. [77] observed an increasein the plasma omega-3 PUFAs, in particular DHA and anincrease in the total omega-3 and omega-6 PUFA ratio in

high-functioning males with autism compared to healthycontrols. Moreover, other lipid biomarkers such as satu-rated and polyunsaturated very long-chain fatty acid-containing phosphatidyl-ethanolamines and DHA-con-taining ethanolamine plasmalogens (PlsEtns) were alsoelevated in the plasma of subjects with autism [78].

The link between altered brain fatty acid metabolismand the occurrence of autism-like behavior has been also


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demonstrated in animal models. For example, variousstudies reported that exposure to environmental agentssuch as propionic acid (PPA), derived from enteric bacte-ria or diet, may result in the appearance of autism-likebehavior in rodents as a result of altered composition ofbrain phospholipids [7981]. Intraventricular infusions

of PPA, reduction in total monounsaturated fatty acids,omega-6 fatty acids and PlsEtns, decreased omega-6/omega-3 ratio, and increased level of total saturated fattyacids, which is consistent with reports observed in theblood of autistic patients [79, 82].

Although there are some differences between the re-ported results, overall these studies show that imbalancesin omega-3 and omega-6 fatty acids exist in patients withautism and likely contribute to the behavioral outcomesin some subsets of autistic patients. Interestingly, admin-istration of supplements containing omega-3 and ome-ga-6 fatty acids resulted in increased level of these fatty

acids in the blood, reduced AA:DHA ratio and improve-ments in several behavioral domains such as eye contact,concentration and motor skills in individuals with au-tism [15]. Supplementation of omega-3 fatty acids hasbeen shown to be effective in ameliorating hyperactivityassociated with autism [83]. Moreover, improvements inbehavior and significant reduction in the elevated DHAand very long-chain fatty acid biomarker level were ob-served in autistic subjects taking carnitine supplements[78]. Previous studies have shown that carnitine, normal-ly required for fatty acid metabolism, is significantly re-duced in some children with autism [84].

The molecular mechanisms for the altered PUFA levelin autistic children are not well understood. Some poten-tial causes have been proposed, including insufficient di-etary intake of PUFA precursors, defects associated withenzymes involved in the conversion of dietary PUFAsinto longer and highly unsaturated derivatives or defi-ciency in the process of incorporation of PUFAs intomembrane phospholipids [73]. It has been suggested thatfatty acid desaturase 1 (FADS1, delta-5-desaturase) andfatty acid desaturase 2 (FADS2, delta-6-desaturase), therate-limiting enzymes in the metabolism of LA and ALA(precursors of AA and DHA), could contribute to lipid

imbalances observed in autism. Interestingly, FADS1 andFADS2 are located in a close proximity to a linkage peakfor autism on chromosome 11q22 [85]. This is an appeal-ing possibility since recent studies have found an associa-tion between genetic variants in FADS1/FADS2 and at-tention deficit hyperactivity disorder [86] and other com-plex diseases, including bipolar disorder or atopicsyndrome [87, 88].

Abnormalities in PG Metabolic Pathway Associated

with ASDs

Phospholipase A2PLA2 is an enzyme involved in the maintenance of

membrane phospholipids. There are three major types of

PLA2enzyme: the calcium-dependent group IV cytosol-ic PLA2, the group II secretory PLA2and the group VIcalcium-independent PLA2 [40, 89]. PLA2 releases AAfrom the sn-2 position of phospholipids, a precursor ofkey lipid mediators such as PGs (fig. 1) [89, 90], and it hasbeen shown to play a key role in neuronal plasticity [91].Stimulation with various neurotransmitters such as glu-tamate [92], N-methyl-D-aspartic acid [93], or -amino-3-hydroxy-5-methyl-4-isoxazole PPA [94] can lead toPLA2activation and release of AA and its metabolites.Additionally, AA and DHA can be released in the pres-ence of stimuli such as cytokines during the inflamma-

tory response [95].Elevated level of PLA2in red blood cells has been as-

sociated with neuropsychiatric disorders such as schizo-phrenia, depression, bipolar disorder, dyslexia and au-tism [14, 96]. A substantial amount of evidence has accu-mulated on elevated plasma levels of PLA2 inschizophrenia patients compared to healthy controls [14,9799]. Three single nucleotide polymorphisms in thegene encoding for cytosolic PLA2 have been linked toschizophrenia and found to play a possible role in the eti-ology of this disorder [100103]. Interestingly, the genesencoding human calcium-independent PLA2and secre-

tory PLA2map to regions on chromosome 8q2324 and7q31, respectively [104, 105], which have been previouslylinked to autism [106108]. It has been suggested that thealtered levels of AA and DHA in individuals with autismdescribed above may be attributed to abnormalities inPLA2. Indeed, significantly increased activity of type IVPLA2has been reported in red blood cells of patients withautism and Aspergers syndrome compared to the con-trols, strengthening the hypothesis that abnormal lipidmetabolism occurs in autism [14, 109]. It has been pro-posed that the observed increased PLA2activity in indi-viduals with autism may be the cause for elevated break-

down of PUFAs and their subsequent reduced incorpora-tion into membrane phospholipids. Overall, the literaturesuggests a link between abnormalities in PLA2enzymesand some psychiatric disorders including autism spec-trum, which substantiates the importance of downstreamlipid signaling molecules in the proper functioning of thenervous system.


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COX EnzymesCOX is the key enzyme that converts AA to PGs [45]

(fig. 1). COX-1 mediates housekeeping functions inmost tissues, and COX-2 is the inducible form and par-ticipates in the inflammatory responses. Growing evi-dence shows that COX-2 plays an important role in the

nervous system via production of downstream signalingmolecules such as PGs [41]. The COX-2/PGE2 pathwayplays an important function in synaptic plasticity andrefining of mature neuronal connections [110112] inaddition to its role during inflammatory response andoxidative stress [113115]. It has been shown that selec-tive COX-2 inhibitors can cause a reduction in long-termpotentiation, which in turn can be reversed by additionof exogenous PGE2, but not PGD2or PGF2, indicatingan important role for COX-2 and its downstream me-tabolites in the nervous system [112]. Interestingly, it hasbeen shown that PGE2can stimulate glutamate release

from astrocytes and modulate the activity of neighbor-ing neurons [116118].

Altered COX-2 level has been reported in neurologicaldisorders, such as stroke and Alzheimers disease or psy-chiatric disorders, indicating that it may contribute to ab-normalities in the nervous system [119122]. The evi-dence for the involvement of the COX-2/PGE2pathway inASDs is now emerging. COX-2 activity and production ofPGs is normally induced by cytokines or proinflamma-tory molecules [119] and altered immune responses havebeen reported in cases of ASD [123, 124], suggesting thepossible involvement of COX-2 in some cases of autism.

More recently, an association between PTGS2 polymor-phism (the gene encoding COX-2 enzyme) and ASDs hasbeen reported [125]. Furthermore, altered laminar pat-tern of COX-2 immunoreactivity in the cortex has beenshown in individuals with Rett syndrome, a form of ASD,further strengthening the evidence for the involvementof abnormal COX-2 signaling in the pathology of the au-tism disorders [126].

PGE2Signaling Pathway and Early DevelopmentPGE2 is a signaling molecule that diffuses rapidly

through the membranes and exerts its diverse effects in

the nervous system through four G-protein coupled EPreceptors: EP1, EP2, EP3 and EP4 [127129]. The role ofPGE2in mediating physiologically important functionssuch as modulation of pain, fever, and inflammatory re-sponse in the nervous system is well established [130135]. In addition, the involvement of PGE2 signaling inearly development including formation of dendriticspines and neuronal plasticity is also emerging [112, 136].

Clinical studies reported that prenatal exposure to thedrug misoprostol, a prostaglandin type E analogue, dur-ing the first trimester of pregnancy may contribute toneurodevelopmental defects, including Mbius syn-drome, a disorder associated with damage to the sixthand seventh cranial nerves, and ASD [137144]. This in-

dicates that early embryonic exposure to misoprostolmay interfere with the PGE2signaling and have neuro-toxic effects on the developing nervous system. Misopro-stol is commonly used as a drug in treating stomach ul-cers [145], inducing labor [146] or in medical terminationof pregnancy [147]. It has been suggested that the embryois most vulnerable to misoprostol during early stages ofpregnancy, 56 weeks after fertilization [148]. Some evi-dence for the molecular effects of misoprostol action oncell function comes from a recent study on Neuro-2acells. Misoprostol and PGE2can elevate intracellular cal-cium level and the amplitude of calcium fluctuations in

growth cones, as well as reduce the number and length ofthe neurite extensions in a dose-dependent manner viaEP receptors [149, 150]. Interestingly, it has been previ-ously shown that dysfunction in calcium regulation mayplay a role in the pathogenesis of ASDs [151157]. Thesestudies suggest that misoprostol may contribute to theneurotoxic effects on neuronal development and com-munication via PGE2pathway.

Various studies have reported a crosstalk betweenCOX-2/PGE2signaling pathway and morphogen mole-cules such as Wnt (wingless) or BMPs (bone morphoge-netic proteins) and their cooperative regulation in neuro-

nal differentiation [158163]. This is interesting becauseWnt and BMP signaling normally play a key role in earlypatterning of the nervous system, neural tube formation,neuronal migration and differentiation, as well as synap-togenesis, synaptic plasticity and synaptic differentiation[164168]. Wnt-2, one of many winglessgenes regulatingcell fate and patterning during early neuronal develop-ment [169], is located in the region of chromosome 7q3133 linked to autism [108, 170, 171]. Interestingly, muta-tions and polymorphism in Wnt-2were found in indi-viduals with autism and severe language abnormalities,respectively, indicating its potential involvement in the

pathogenesis of ASDs [172]. Wnt signaling pathways alsoplay an important role in axon guidance and synapse for-mation, which involves the release of calcium from intra-cellular stores for growth cone remodeling and synapto-genesis [173]. PGE2- or misoprostol-induced alteration ofcalcium fluctuation in growth cones as shown by Tamijiand Crawford [174, 175] may potentially interfere withWnt signaling pathway and affect differentiation. It has


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been shown that Ca2+signaling triggered by neuronal ac-tivity mediates synthesis and secretion of CREB-depen-dent transcription Wnt-2and contributes to proper den-dritic outgrowth and branching, suggesting the impor-tance of the protein in neuronal development [176].Moreover, infections associated with the development of

gastric cancer can induce the COX-2/PGE2 signalingpathway by significantly increasing the level of PGE2through induction of COX-2 and mPGES-1, membrane-associated PGE synthase-1, and subsequent activation ofWnt and inhibition of BMP signaling pathways [158]. Ithas also been reported that increased transcription ofCOX-2 gene and PGE2level was induced by Wnt signal-ing pathway in epithelial cells and cancer stem cells, fur-ther strengthening the cooperative interaction betweenthese pathways [160, 163, 177].

The expression of four EP receptors transcripts (EP1,EP2, EP3and EP4) significantly increases in the mouse

during embryonic day 1115 (early neurogenesis), indi-cating that the PGE2signaling pathway may have an im-portant role during early development [174]. Many brainstructures, such as medulla, pons and cerebellum, start todevelop at the early stages of the neurogenesis (embry-onic day 12) and others, such as, hippocampus, hypo-thalamus, thalamus and entorhinal cortex that begin de-veloping at around day 15 [178]. The early brain pathol-ogy in many of these regions has been reported in autism[179181]. A direct involvement of COX-2/PGE2signal-ing pathway in the development of these structures stillremains to be established.

Contribution of Oxidative Stress and Lipid

Peroxidation in the Etiology of ASDs

Membrane phospholipids are primary targets of oxi-dative stress, a state in which there is an imbalance be-tween the production of reactive oxygen species and theantioxidant capacity of the cells, including enzymaticand nonenzymatic mechanisms [182]. Reactive oxygenspecies may induce lipid peroxidation, the oxidativebreakdown of lipids, which can disrupt the composition

of membrane phospholipids and alter neuronal function[183, 184]. Presence of double bonds in membrane phos-pholipids makes them particularly susceptible to oxida-tive damage [185, 186]. The brain is considered vulnerableto oxidative stress particularly during its early develop-ment because of high lipid content and limited antioxi-dant capacity making children more susceptible to in-sults [187, 188]. Purkinje cells in the cerebellum, for in-

stance, are particularly vulnerable to oxidative stress[189, 190]. Interestingly, significant loss of Purkinje cellsaccompanied by gliosis was determined in some childrenwith autism [191, 192].

Various studies have reported elevation of lipid per-oxidation markers accompanied by a reduction in anti-

oxidant enzymes in individuals with autism, suggestinga contribution of altered lipid signaling to the pathogen-esis of the disorder [11, 12, 193, 194]. Glutathione (GSH)is one of the main antioxidants that protect against lipidperoxidation and oxidative stress in the neurons [195].Lower levels of reduced GSH (active form) during earlypostnatal life indicate that the developing brain might bemore susceptible to oxidative damage [196]. It has beenshown that children with autism have lower levels of thereduced form of GSH, and therefore a decreased ratio ofGSH to the oxidized form disulfide GSH. Additionally, adeficiency in methionine and cysteine (precursors in the

production of GSH) has been detected in these patients,suggesting that they might be more prone to oxidativestress and at a greater risk of developing brain disorders[12, 78, 197199]. Several polymorphisms affecting me-thionine and GSH metabolism have also been reported incases of autism, suggesting a possibility of genetic influ-ences [197, 200].

Interestingly, children with autism exposed to mercu-ry showed signif icantly decreased level of GSH [201]. Twostudies of children in the San Francisco area and Texasfound that children living in close proximity to indus-trial power plant sources of mercury had significantly

higher prevalence of autism [202, 203]. Evidence of expo-sure to mercury due to maternal dental amalgam or vac-cination has been also reported in some cases of autism[201]. Pre- or postnatal exposure to toxic metals such asmercury has been shown to contribute to increased oxi-dative stress and toxic effects on the developing nervoussystem [204].

Junaid et al. [205] characterized a single nucleotidepolymorphism (C419A) in another antioxidant enzymeglyoxalase 1 (Glo1) and showed significantly higher fre-quency for the A419 allele in patients with autism, sug-gesting that it might be a predisposing factor in the etiol-

ogy of the disorder. In addition, a reduced Glo1 enzymeactivity has been also reported in the brain of autismsubjects [205]. Interestingly, Glo1 is located in close prox-imity to an autism locus on chromosome 6p identifiedby linkage and association studies, strengthening a pos-sible involvement of Glo1 in autism [206, 207]. Further-more, the level of malonyldialdehyde, the end productsof lipid peroxidation, as well as antioxidant proteins ce-


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ruloplasmin and transferrin, have been shown to be sig-nificantly elevated in the plasma or urine samples of au-tistic children compared to healthy controls [10, 11, 194,208].

In general, evidence for altered antioxidant capacityand increased oxidative stress in individuals with autism

is compelling. Emerging evidence in the recent reportsalso shows a role played by prostanoid metabolites in theincreased oxidative damage in some patients with au-tism. The levels of a lipid peroxidation biomarker 2,3-dinor-thromboxane (TxB2), the metabolite of the TxA2derived from platelets, and 6-ketoprostaglandin PGF1(6-keto-PGF1), the metabolite of the endothelium pros-tacyclin (or PGI2; fig. 1) have been significantly elevatedin children with autism [209]. Moreover, 8-isoprostane-F2 (8-iso-PGF2) and isoprostane F2-VI (iPF2-VI),by-products of prostaglandin F2(PGF2) peroxidationproduced in a nonenzymatic oxidation of AA (fig. 1),

have also been shown to be significantly higher in redblood cells or urine sample of children with autism com-pared to the healthy controls [10, 209]. Elevated level ofiPF2was also found in plasma of children with autism[74] and Rett syndrome patients [210]. The increased ac-cumulation of F2-isoprostanes, which normally pro-motes platelet aggregation and vasoconstriction [211],might explain the altered platelet reactivity in childrenwith autism and may contribute to the vascular abnor-malities in these patients [212, 213]. Although the effectsof the elevated level of PG metabolites in the nervoussystem need to be elucidated, the reported findings fur-

ther support the presence of altered lipid biogenesis inASDs.

Involvement of Immunological Factors

Emerging evidence suggests that immunological fac-tors might have an effect on brain development throughmodification of COX-2/PG signaling, and play a role inthe pathology of some mental disorders [214217]. COX-derived lipid mediators such as PGE2or PGF2have beenshown to be significantly increased following infections

[218220] or inflammations, especially during pregnan-cy [221223]. Several clinical studies and case reportshave shown possible contributions of viral infections andabnormal immune response in some cases of autism[224]. It has been shown that prenatal and postnatal in-fections may trigger autoimmune responses in autism[225227] or stimulate immune responses in the motheror offspring [228233].

Prenatal and postnatal exposure to viral infectionssuch as measles [234], rubella [235], herpes viruses [236],and cytomegalovirus [237, 238] has been associated withautism. Moreover, polyomavirus genome was detected inpostmortem brain tissues from individuals with autism,indicating the presence of infection in the brain of these

patients [239]. Although the molecular mechanisms bywhich viral infections contribute to the pathology of au-tism via PGE2 signaling are still largely unknown andoften inconclusive, the animal models provide some in-direct evidence that altered immune responses due to in-fections might contribute to the development of autism.In animal models, pre- and postnatal infections havebeen shown to lead to immunological changes in off-spring, gene alterations in the brain and specific behav-ioral changes similar to those found in autism spectrum[216, 217, 240243]. Prenatal exposure of pregnant miceto viral infections also results in increased pyramidal cell

density, reduced size of the Purkinje cells of the cerebel-lum and brain enlargement in the embryos [244]. Similarchanges were observed in the brain of individuals withautism [179, 245, 246].

The immune system, including its inflammatory com-ponents, is essential in defense against pathogens. Ome-ga-6 and omega-3 PUFA eicosanoids play a central role inregulating immune and inflammatory responses [247,248]. Eicosanoids derived from omega-6 PUFAs (AA)have proinflammatory and immunoactive role, whereaseicosanoids derived from omega-3 PUFAs (EPA andDHA) have anti-inflammatory properties. PGE2, the

most abundant eicosanoid produced predominantlyfrom AA, induces cytokine expression [249252]. A num-ber of case studies provide evidence that dysfunction ofthe immune system such as generation of antibodies orstimulation of cytokine production may result in pathol-ogies of autism [123]. Elevated levels of plasma immuno-globin classes have been reported in some children withautism, indicating altered susceptibility to infections[229, 253, 254]. Production of proinflammatory cyto-kines such as tumor necrosis factor-, interleukin-6 andinterferon-, have been elevated in the blood of autisticchildren compared to healthy controls [255261]. Immu-

nocytochemical studies using brain tissues from individ-uals with autism showed that neuroglia-derived macro-phage chemoattractant protein-1 and tumor growth fac-tor-1 were the most prevalent cytokines, indicating thatimmune dysfunction may result in CNS pathology andcontribute to the development of autism [262]. Elevatedcytokine production can alter CNS function and devel-opment [224]. For example, in cultured rat embryonic


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hippocampal neurons interferon- inhibits dendriticoutgrowths, thereby decreasing synaptic formation [263].Interestingly, reduced dendritic branching has beenshown in the hippocampus of autistic patients [264]. Re-cent studies indicate that gastrointestinal inflammationcan also affect CNS via cytokines and contribute to the

development of ASDs [265267]. In animals, intracere-broventricular injections of PPA (the metabolic end prod-uct of enteric bacteria) result in astrogliosis in the brainof the animals, suggesting neuroinf lammation as a resultof activation of CNS innate immune cells [81]. Thesemodels of infection in developing animals provide evi-dence that viral infections and the resulting immune re-sponse may alter neuronal development and lead to be-havioral abnormalities seen in autism. Further studiesare required to provide a direct link for the effect of im-munological factors on the function of the COX-2/PGpathway and their contribution to the pathology of au-

tism.

Conclusions

Autism is a complex neurodevelopmental disordercaused by interaction between genetic and environmen-tal factors. Although autism is behaviorally defined andits biochemical defects are stil l not well understood, sev-

eral lines of research support the hypothesis that childrenwith autism show higher rates of in vivo lipid metabolismthan healthy controls. The provided evidence shows thatimpairment at various steps of the lipid metabolic path-ways may contribute to the development of autism. Thesestudies collectively suggest that lipid signaling may playan important role in the pre- and postnatal period, andalterations of this pathway can negatively impact the de-velopment of the nervous system and lead to autism.Identification of various genetic or environmental factorscontributing to deficits in these lipid signaling pathwaysin individuals with autism will likely be important for

understanding the molecular mechanisms of the disor-der and the development of novel therapeutic and preven-tion strategies early in life.

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