Autism and cholesterol metabolism
Autism spectrum disorders (ASDs) are a group of developmental psychiatric disorders characterized by impaired social interaction and communication, and by restricted, repetitive and stereotyped behaviors and interests (Zoghbi and Bear, 2012; Ebert and Greenberg, ; Huguet et al., ). Since the features of ASDs usually manifest at the early childhood when sensory experience is modifying the development and balance of excitatory and inhibitory synapses, it has been hypothesized that ASDs may be due to the disruption of experience dependent synaptic development and function, resulting in an imbalance between excitation and inhibition in brain (Auerbach et al., ; Zoghbi and Bear, 2012; Delorme et al., ; Wang and Doering, 2013). Although genetic causes have been identified in many individuals with ASDs, the details about how those causal genes converge on common pathways to alter synaptic homeostasis in ASDs still need to be investigated. Recently, Buchovecky et al. described disturbances in cholesterol homeostasis in animal model of the ASD Rett syndrome (RTT), giving rise to an exciting prospect that changes in cholesterol metabolism might underlie the development of ASDs (Buchovecky et al., ).
Cholesterol, an essential cell membrane component, influences the establishment and maintenance of synaptic connection and glial cell development in the nervous system. Balanced cholesterol homeostasis is an important aspect of nervous system function (Mauch et al., ; Pfrieger, 2003; Linetti et al., ; Pfrieger and Ungerer, 2011; Mathews et al., ) (Figure 1A). Perturbed cholesterol homeostasis can affect neural development and synaptogenesis and result in synaptic dysfunction, thus may lead to disorders of nervous system (Simons and Ehehalt, 2002; Linetti et al., ; Pani et al., ; Karasinska and Hayden, ). Evidence from patients indicates that cholesterol homeostasis could be altered in autistic disorders. The Smith-Lemli-Opitz Syndrome (SLOS), a genetic condition of impaired cholesterol biosynthesis due to mutations of the 7-dehydrocholesterol reductase gene (DHCR7), has been found to be associated with autism, supporting genetic defects in cholesterol metabolism can cause autism (Sikora et al., 2006; Bukelis et al., ; Diaz-Stransky and Tierney, ). Abnormal cholesterol metabolism has also been observed in patients with the ASD Asperger syndrome and other nonsyndromic ASDs, suggesting different abnormalities of cholesterol metabolism may exist in ASDs (Tierney et al., 2006; Dziobek et al., ). However, little is known about the mechanisms that mediate the abnormal cholesterol metabolism in these ASD conditions.
Figure 1
RTT is caused largely by mutations in the X-linked methyl CpG-binding protein 2 gene (MECP2) (Baker et al., ; Lyst et al., ; Xu and Pozzo-Miller, 2013). In Mecp2 mutant mice, Buchovecky et al. found that the expression of genes (Hmgcr, Sqle and Cyp46a1) which encode key enzymes (3-hydroxy-3-methylglutaryl-CoA reductase, squalene epoxidase, CYP46A1) in the cholesterol metabolic pathway and cholesterol concentrations are altered in the brain in a development dependent manner (Buchovecky et al., ). Their study indicates that loss of Mecp2 disrupts cholesterol homeostasis, suggesting abnormal cholesterol metabolism might be involved in the pathogenesis of RTT (Nagy and Ackerman, ). It thus links the autism associated gene to cholesterol metabolism, providing further insights into the relationship between cholesterol metabolism and ASDs.
Cholesterol, lipid rafts and synaptic plasticity
Disturbances in cholesterol homeostasis in ASDs raise the question of how changes in cholesterol metabolism might be involved in the development of autism. Cholesterol is not uniformly distributed in biological membranes, but concentrated in lipid rafts, together with other lipids like sphingolipids (Pfrieger, 2003; Fielding and Fielding, ; Korade and Kenworthy, ; Pfrieger and Ungerer, 2011). Lipid rafts, which are believed to act as platforms for cellular signal transduction, have been shown to play roles in synaptic plasticity and contribute to neuropathologies, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington disease (HD) (Tsui-Pierchala et al., 2002; Pfrieger, 2003; Korade and Kenworthy, ; Pani et al., ; Karasinska and Hayden, ; Sebastiao et al., 2012). Cholesterol is a key component of lipid rafts; its depletion disrupts lipid rafts and leads to synaptic dysfunction or loss of synapses (Mauch et al., ; Fielding and Fielding, ; Korade and Kenworthy, ; Linetti et al., ; Pfrieger and Ungerer, 2011; Pristera and Okuse, 2011; Sebastiao et al., 2012). Since altered synaptic function is the common basis for ASDs (Santoro et al., 2012; Zoghbi and Bear, 2012; Delorme et al., ; Ebert and Greenberg, ; Wang and Doering, 2013), it is likely that abnormal cholesterol metabolism might be implicated in autism through lipid raft disarrangements.
Lipid rafts are specialized membrane structures that form an organized portion of the membrane with concentrated signaling molecules and link to the cytoskeleton (Simons and Toomre, 2000; Simons and Ehehalt, 2002; Tsui-Pierchala et al., 2002; Fielding and Fielding, ; Allen et al., ; Korade and Kenworthy, ; Lingwood and Simons, ; Simons and Sampaio, 2011). The synapses, both the presynaptic and postsynaptic sites, are highly enriched in lipid rafts. Lipid rafts not only contribute to neurotransmitter exocytosis in presynaptic terminals, but also postsynapticly modulate neuronal signaling through clustering of neurotransmitter receptors, ion channels and components of downstream effectors (Tsui-Pierchala et al., 2002; Korade and Kenworthy, ; Linetti et al., ; Pfrieger and Ungerer, 2011; Pristera and Okuse, 2011; Sebastiao et al., 2012) (Figure 1A). The postsynaptic density (PSD), which is a massive multi-protein complex whose functions include positioning signaling molecules for synaptic plasticity, could be physically associated with lipid rafts (Hering et al., ; Sheng and Hoogenraad, 2007; Delint-Ramirez et al., ; Sheng and Kim, 2011; Suzuki et al., 2011; Liu et al., ). Numerous PSD proteins such as NMDA receptors (NR1, NR2A and NR2B), AMPA receptors (GluR1 and GluR2), metabotropic glutamate receptors (mGluRs), PSD-93/95, CaMKII, and cadherin, are associated with synaptic lipid rafts; notably, PSD-95 binds to the postsynaptic neuroligins which interact with the presynaptic neurexins, providing a transsynaptic link between PSD and presynaptic active zone (Hering et al., ; Delint-Ramirez et al., ; Sheng and Kim, 2011; Suzuki et al., 2011; Liu et al., ). The association of PSD with lipid rafts might be important in signal integration and synaptic function. Accumulating evidence has indicated that precise localization of neurotransmitter receptors, transporters, ion channels and other synaptic proteins in lipid rafts can be regulated by cholesterol and this regulation is critical for synaptic plasticity (Tsui-Pierchala et al., 2002; Hering et al., ; Allen et al., ; Linetti et al., ; Pfrieger and Ungerer, 2011; Pristera and Okuse, 2011; Sebastiao et al., 2012) (Figure 1A). Importantly, many of the lipid rafts associated signaling molecules or pathways have been found to be implicated in autism (Tsui-Pierchala et al., 2002; Allen et al., ; Pristera and Okuse, 2011; Sebastiao et al., 2012; Zoghbi and Bear, 2012; Delorme et al., ; Ebert and Greenberg, ; Huguet et al., ; Schmunk and Gargus, 2013; Won et al., 2013) (Summarized in Figure 1B). Therefore, it is reasonable to postulate that lipid rafts might serve as a platform where cholesterol imbalance eventually causes neuronal and synaptic deficits in ASDs (Wassif et al., 2001; Waage-Baudet et al., 2005; Lee and Tierney, ).
Cholesterol, lipid rafts and ASD therapy
Interestingly, genetic or pharmacological manipulation of cholesterol metabolism has been found to alleviate ASD associated animal behaviors. In the aforementioned study, a mutagenesis screen in Mecp2 mutant mice has identified that a nonsense mutation in SQLE, which is an obligate rate-limiting enzyme in cholesterol biosynthesis, diminished some of RTT related phenotypes (Buchovecky et al., ). Statins reduce cholesterol synthesis by interfering with cholesterol synthesis through competitive inhibition of HMGCR. Since cholesterol synthesis is functionally tied to the mevalonate pathway, statins also inhibit the synthesis of isoprenoid intermediates farnesyl pyrophosphate and ubiquinones, and thus affect protein modifications such as prenylation, which are important for the localization and function of signaling proteins such as Ras (van der Most et al., 2009; Nagy and Ackerman, ). Due to their impact on cholesterol synthesis and protein modification, statins perturb the composition and properties of lipid rafts (van der Most et al., 2009). These drugs might exert effect on RTT animals as manipulation of SQLE did. As expected, treatment with statins did ameliorate metabolic symptoms and improved animal motor coordination and activity of the Mecp2 mutant mice (Buchovecky et al., ).
Noteworthily, the effect of statin treatment has also been observed in animal models of other ASDs, including fragile X syndrome and neurofibromatosis type 1 (Li et al., ; Osterweil et al., ). Group I mGluRs (mGluR1 and mGluR5) are present in lipid rafts and play critical roles in activity dependent synaptic plasticity (Sebastiao et al., 2012; Wang and Zhuo, 2012). In animal models of fragile X syndrome, the activity of group I mGluRs is abnormally enhanced, which is causally linked to the pathogenesis of this disease condition (Bear et al., ; Wang et al., 2008a; Santoro et al., 2012; Zoghbi and Bear, 2012). The scaffolding protein caveolin in lipid rafts, alteration in membrane cholesterol content or perturbation of lipid rafts have been shown to be able to regulate group I mGluR trafficking and downstream signaling pathways such as mitogen-activated protein Kinases (MAPKs) (Francesconi et al., ; Kumari et al., ). In cultured neurons from fragile X mice, group I mGluR dependent signaling was attenuated by statins (Kumari et al., ). Consistently, application of statins reduced abnormally elevated protein synthesis and mGluR-long term depression (LTD) in hippocampal slices of fragile X mice, attenuated audiogenic seizures and corrected the hyperexcitability in the visual cortex of these animals (Osterweil et al., ). Apart from inhibition of signaling molecules such as Ras signaling for protein synthesis which has been suggested by the investigators to underlie the observed effects (Li et al., ; Osterweil et al., ), statins may also benefit ASD conditions through their action on the cholesterol-lipid raft-mGluR pathway. Taken together, these studies further support defective cholesterol homeostasis may underlie the ASD phenotypes, suggesting that cholesterol metabolism and lipid rafts could be therapeutic targets for ASDs. Considering the complexity and heterogeneity of autism, it will be necessary to assess in future studies the effect of statin treatment on the full spectrum of ASD phenotypes.
Challenges and open questions
It is important to note, cholesterol may regulate protein function not only through altering lipid rafts but also by direct interactions with the proteins. However, it is very challenging to discriminate between these possibilities for any specific type of protein because it is unreasonable to test the effect of cholesterol on the function of a membrane protein in an environment without lipid rafts (Levitan et al., ). Since cholesterol metabolism in brain depends on the cooperation between neurons and astrocytes, it will be necessary to examine or manipulate cholesterol metabolism and lipid rafts in individual cell types (neurons or glial cells) of the diseased brain (Korade and Kenworthy, ; Pfrieger and Ungerer, 2011). In view of that lipid rafts could be potentially modifiable by dietary cholesterol, gangliosides, and fatty acids (Yaqoob and Shaikh, 2010), the relevance and significance of those dietary supplements for ASD treatment remains to be determined. Although statins have shown to be promising for ASD therapy, the timing, dosage and ideal drugs will need to be identified in animal models or other preclinical trials to facilitate the design of individualized therapeutic strategy (Buchovecky et al., ; Nagy and Ackerman, ; Osterweil et al., ).
Despite the controversies in lipid raft research, it is now clear that lipid rafts which represent dynamic structural components of cellular membranes do play roles in neuronal signaling and that dysregulation of lipid rafts can lead to diseases (Allen et al., ; Korade and Kenworthy, ; Pfrieger and Ungerer, 2011; Pristera and Okuse, 2011; Sebastiao et al., 2012). Due to complexity of ASD pathology and etiology, the involvement of lipid rafts in these disease conditions is not simple. The disturbed cholesterol metabolism or lipid raft aberrance may not exist in all cases or every stage of the ASDs. Thus, lipid rafts should not be seen as the simplistic link between genetic defects and synaptic dysfunction in autism. Additional studies are definitely required to investigate cholesterol metabolism and lipid raft abnormalities in ASDs and their relevance to the pathophysiology and treatment of these neurodevelopmental disorders. These studies will need to combine biochemical, biophysical, imaging, behavioral, genetic and pharmacological techniques to advance our understanding and therapeutics of autism.
Statements
Acknowledgments
Hansen Wang was supported by the National Natural Science Foundation of China (NSFC, No.30200152) for Rett syndrome studies and the Fragile X Research Foundation of Canada.
References
1
AllenJ. A.Halverson-TamboliR. A.RasenickM. M. (2007). Lipid raft microdomains and neurotransmitter signalling. Nat. Rev. Neurosci. 8, 128–140. 10.1038/nrn2059
2
AuerbachB. D.OsterweilE. K.BearM. F. (2011). Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature480, 63–68. 10.1038/nature10658
3
BakerS. A.ChenL.WilkinsA. D.YuP.LichtargeO.ZoghbiH. Y. (2013). An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders. Cell152, 984–996. 10.1016/j.cell.2013.01.038
4
BearM. F.HuberK. M.WarrenS. T. (2004). The mGluR theory of fragile X mental retardation. Trends Neurosci. 27, 370–377. 10.1016/j.tins.2004.04.009
5
BuchoveckyC. M.TurleyS. D.BrownH. M.KyleS. M.McDonaldJ. G.LiuB.et al. (2013). A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome. Nat. Genet. 45, 1013–1020. 10.1038/ng.2714
6
BukelisI.PorterF. D.ZimmermanA. W.TierneyE. (2007). Smith-Lemli-Opitz syndrome and autism spectrum disorder. Am. J. Psychiatry164, 1655–1661. 10.1176/appi.ajp.2007.07020315
7
Delint-RamirezI.FernandezE.BayesA.KicsiE.KomiyamaN. H.GrantS. G. (2010). In vivo composition of NMDA receptor signaling complexes differs between membrane subdomains and is modulated by PSD-95 and PSD-93. J. Neurosci. 30, 8162–8170. 10.1523/JNEUROSCI.1792-10.2010
8
DelormeR.EyE.ToroR.LeboyerM.GillbergC.BourgeronT. (2013). Progress toward treatments for synaptic defects in autism. Nat. Med. 19, 685–694. 10.1038/nm.3193
9
Diaz-StranskyA.TierneyE. (2012). Cognitive and behavioral aspects of Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. C Semin. Med. Genet. 160C, 295–300. 10.1002/ajmg.c.31342
10
DziobekI.GoldS. M.WolfO. T.ConvitA. (2007). Hypercholesterolemia in Asperger syndrome: independence from lifestyle, obsessive-compulsive behavior, and social anxiety. Psychiatry Res. 149, 321–324. 10.1016/j.psychres.2006.02.003
11
EbertD. H.GreenbergM. E. (2013). Activity-dependent neuronal signalling and autism spectrum disorder. Nature493, 327–337. 10.1038/nature11860
12
FieldingC. J.FieldingP. E. (2004). Membrane cholesterol and the regulation of signal transduction. Biochem. Soc. Trans. 32, 65–69. 10.1042/BST0320065
13
FrancesconiA.KumariR.ZukinR. S. (2009). Regulation of group I metabotropic glutamate receptor trafficking and signaling by the caveolar/lipid raft pathway. J. Neurosci. 29, 3590–3602. 10.1523/JNEUROSCI.5824-08.2009
14
HeringH.LinC. C.ShengM. (2003). Lipid rafts in the maintenance of synapses, dendritic spines, and surface AMPA receptor stability. J. Neurosci. 23, 3262–3271.
15
HuguetG.EyE.BourgeronT. (2013). The genetic landscapes of autism spectrum disorders. Annu. Rev. Genomics Hum. Genet. 14, 191–213. 10.1146/annurev-genom-091212-153431
16
KarasinskaJ. M.HaydenM. R. (2011). Cholesterol metabolism in Huntington disease. Nat. Rev. Neurol. 7, 561–572. 10.1038/nrneurol.2011.132
17
KoradeZ.KenworthyA. K. (2008). Lipid rafts, cholesterol, and the brain. Neuropharmacology55, 1265–1273. 10.1016/j.neuropharm.2008.02.019
18
KrummN.O'RoakB. J.ShendureJ.EichlerE. E. (2014). A de novo convergence of autism genetics and molecular neuroscience. Trends Neurosci. 37, 95–105. 10.1016/j.tins.2013.11.005
19
KumariR.CastilloC.FrancesconiA. (2013). Agonist-dependent signaling by group I metabotropic glutamate receptors is regulated by association with lipid domains. J. Biol. Chem. 288, 32004–32019. 10.1074/jbc.M113.475863
20
LeeR. W.TierneyE. (2011). Hypothesis: the role of sterols in autism spectrum disorder. Autism Res. Treat. 2011:653570. 10.1155/2011/653570
21
LevitanI.FangY.Rosenhouse-DantskerA.RomanenkoV. (2010). Cholesterol and ion channels. Subcell. Biochem. 51, 509–549. 10.1007/978-90-481-8622-8_19
22
LiW.CuiY.KushnerS. A.BrownR. A.JentschJ. D.FranklandP. W.et al. (2005). The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr. Biol. 15, 1961–1967. 10.1016/j.cub.2005.09.043
23
LinettiA.FratangeliA.TavernaE.ValnegriP.FrancoliniM.CappelloV.et al. (2010). Cholesterol reduction impairs exocytosis of synaptic vesicles. J. Cell Sci. 123, 595–605. 10.1242/jcs.060681
24
LingwoodD.SimonsK. (2010). Lipid rafts as a membrane-organizing principle. Science327, 46–50. 10.1126/science.1174621
25
LiuQ.YaoW. D.SuzukiT. (2013). Specific interaction of postsynaptic densities with membrane rafts isolated from synaptic plasma membranes. J. Neurogenet. 27, 43–58. 10.3109/01677063.2013.772175
26
LystM. J.EkiertR.EbertD. H.MerusiC.NowakJ.SelfridgeJ.et al. (2013). Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat. Neurosci. 16, 898–902. 10.1038/nn.3434
27
MathewsE. S.MawdsleyD. J.WalkerM.HinesJ. H.PozzoliM.AppelB. (2014). Mutation of 3-hydroxy-3-methylglutaryl CoA synthase I reveals requirements for isoprenoid and cholesterol synthesis in oligodendrocyte migration arrest, axon wrapping, and myelin gene expression. J. Neurosci. 34, 3402–3412. 10.1523/JNEUROSCI.4587-13.2014
28
MauchD. H.NaglerK.SchumacherS.GoritzC.MullerE. C.OttoA.et al. (2001). CNS synaptogenesis promoted by glia-derived cholesterol. Science294, 1354–1357. 10.1126/science.294.5545.1354
29
MurdochJ. D.StateM. W. (2013). Recent developments in the genetics of autism spectrum disorders. Curr. Opin. Genet. Dev. 23, 310–315. 10.1016/j.gde.2013.02.003
30
NagyG.AckermanS. L. (2013). Cholesterol metabolism and Rett syndrome pathogenesis. Nat. Genet. 45, 965–967. 10.1038/ng.2738
31
OsterweilE. K.ChuangS. C.ChubykinA. A.SidorovM.BianchiR.WongR. K.et al. (2013). Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron77, 243–250. 10.1016/j.neuron.2012.01.034
32
PaniA.MandasA.DessiS. (2010). Cholesterol, Alzheimer's disease, prion disorders: a menage a trois?Curr. Drug Targets11, 1018–1031. 10.2174/138945010791591386
33
PersicoA. M.NapolioniV. (2013). Autism genetics. Behav. Brain Res. 251, 95–112. 10.1016/j.bbr.2013.06.012
34
PfriegerF. W. (2003). Cholesterol homeostasis and function in neurons of the central nervous system. Cell. Mol. Life Sci. 60, 1158–1171. 10.1007/s00018-003-3018-7
35
PfriegerF. W.UngererN. (2011). Cholesterol metabolism in neurons and astrocytes. Prog. Lipid Res. 50, 357–371. 10.1016/j.plipres.2011.06.002
36
PristeraA.OkuseK. (2011). Building excitable membranes: lipid rafts and multiple controls on trafficking of electrogenic molecules. Neuroscientist18, 70–81. 10.1177/1073858410393977
37
RonemusM.IossifovI.LevyD.WiglerM. (2014). The role of de novo mutations in the genetics of autism spectrum disorders. Nat. Rev. Genet. 15, 133–141. 10.1038/nrg3585
38
SantoroM. R.BrayS. M.WarrenS. T. (2012). Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu. Rev. Pathol. 7, 219–245. 10.1146/annurev-pathol-011811-132457
39
SchmunkG.GargusJ. J. (2013). Channelopathy pathogenesis in autism spectrum disorders. Front. Genet. 4:222. 10.3389/fgene.2013.00222
40
SebastiaoA. M.Colino-OliveiraM.Assaife-LopesN.DiasR. B.RibeiroJ. A. (2012). Lipid rafts, synaptic transmission and plasticity: impact in age-related neurodegenerative diseases. Neuropharmacology64, 97–107. 10.1016/j.neuropharm.2012.06.053
41
ShengM.HoogenraadC. C. (2007). The postsynaptic architecture of excitatory synapses: a more quantitative view. Annu. Rev. Biochem. 76, 823–847. 10.1146/annurev.biochem.76.060805.160029
42
ShengM.KimE. (2011). The postsynaptic organization of synapses. Cold Spring Harb. Perspect. Biol. 3:a005678. 10.1101/cshperspect.a005678
43
SikoraD. M.Pettit-KekelK.PenfieldJ.MerkensL. S.SteinerR. D. (2006). The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. A140, 1511–1518. 10.1002/ajmg.a.31294
44
SimonsK.EhehaltR. (2002). Cholesterol, lipid rafts, and disease. J. Clin. Invest. 110, 597–603. 10.1172/JCI0216390
45
SimonsK.SampaioJ. L. (2011). Membrane organization and lipid rafts. Cold Spring Harb. Perspect. Biol. 3:a004697. 10.1101/cshperspect.a004697
46
SimonsK.ToomreD. (2000). Lipid rafts and signal transduction. Nat. Rev. Mol. Cell Biol. 1, 31–39. 10.1038/35036052
47
SuzukiT.ZhangJ.MiyazawaS.LiuQ.FarzanM. R.YaoW. D. (2011). Association of membrane rafts and postsynaptic density: proteomics, biochemical, and ultrastructural analyses. J. Neurochem. 119, 64–77. 10.1111/j.1471-4159.2011.07404.x
48
TierneyE.BukelisI.ThompsonR. E.AhmedK.AnejaA.KratzL.et al. (2006). Abnormalities of cholesterol metabolism in autism spectrum disorders. Am. J. Med. Genet. B Neuropsychiatr. Genet. 141B, 666–668. 10.1002/ajmg.b.30368
49
Tsui-PierchalaB. A.EncinasM.MilbrandtJ.JohnsonE. M.Jr. (2002). Lipid rafts in neuronal signaling and function. Trends Neurosci. 25, 412–417. 10.1016/S0166-2236(02)02215-4
50
van der MostP. J.DolgaA. M.NijholtI. M.LuitenP. G.EiselU. L. (2009). Statins: mechanisms of neuroprotection. Prog. Neurobiol. 88, 64–75. 10.1016/j.pneurobio.2009.02.002
51
Waage-BaudetH.DuntyW. C.Jr.DehartD. B.HillerS.SulikK. K. (2005). Immunohistochemical and microarray analyses of a mouse model for the smith-lemli-opitz syndrome. Dev. Neurosci. 27, 378–396. 10.1159/000088453
52
WangH.DoeringL. C. (2013). Reversing autism by targeting downstream mTOR signaling. Front. Cell. Neurosci. 7:28. 10.3389/fncel.2013.00028
53
WangH.KimS. S.ZhuoM. (2010). Roles of fragile X mental retardation protein in dopaminergic stimulation-induced synapse-associated protein synthesis and subsequent alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-4-propionate (AMPA) receptor internalization. J. Biol. Chem. 285, 21888–21901. 10.1074/jbc.M110.116293
54
WangH.WuL. J.KimS. S.LeeF. J.GongB.ToyodaH.et al. (2008b). FMRP acts as a key messenger for dopamine modulation in the forebrain. Neuron59, 634–647. 10.1016/j.neuron.2008.06.027
55
WangH.WuL. J.ZhangF.ZhuoM. (2008a). Roles of calcium-stimulated adenylyl cyclase and calmodulin-dependent protein kinase IV in the regulation of FMRP by group I metabotropic glutamate receptors. J. Neurosci. 28, 4385–4397. 10.1523/JNEUROSCI.0646-08.2008
56
WangH.ZhuoM. (2012). Group I metabotropic glutamate receptor-mediated gene transcription and implications for synaptic plasticity and diseases. Front. Pharmacol. 3:189. 10.3389/fphar.2012.00189
57
WassifC. A.ZhuP.KratzL.KrakowiakP. A.BattaileK. P.WeightF. F.et al. (2001). Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith–Lemli–Opitz syndrome. Hum. Mol. Genet. 10, 555–564. 10.1093/hmg/10.6.555
58
WonH.MahW.KimE. (2013). Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses. Front. Mol. Neurosci. 6:19. 10.3389/fnmol.2013.00019
59
XuX.Pozzo-MillerL. (2013). A novel DNA-binding feature of MeCP2 contributes to Rett syndrome. Front. Cell. Neurosci. 7:64. 10.3389/fncel.2013.00064
60
YaqoobP.ShaikhS. R. (2010). The nutritional and clinical significance of lipid rafts. Curr. Opin. Clin. Nutr. Metab. Care13, 156–166. 10.1097/MCO.0b013e328335725b
61
ZoghbiH. Y.BearM. F. (2012). Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb. Perspect. Biol. 4:a009886. 10.1101/cshperspect.a009886
Summary
Keywords
cholesterol, lipid rafts, autism spectrum disorders, synaptic plasticity, fragile X syndrome, Rett syndrome, FMRP, statins
Citation
Wang H (2014) Lipid rafts: a signaling platform linking cholesterol metabolism to synaptic deficits in autism spectrum disorders. Front. Behav. Neurosci. 8:104. doi: 10.3389/fnbeh.2014.00104
Received
30 January 2014
Accepted
12 March 2014
Published
27 March 2014
Volume
8 - 2014
Edited by
Francesca Cirulli, Istituto Superiore di Sanità , Italy
Reviewed by
Laura Ricceri, Istituto Superiore di Sanità , Italy
Copyright
© 2014 Wang.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: hansen.wang@utoronto.ca
This article was submitted to the journal Frontiers in Behavioral Neuroscience.
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.