Autism Spectrum Disorder: Signaling Pathways and Prospective Therapeutic Targets

Abstract

The Autism Spectrum Disorder (ASD) consists of a prevalent and heterogeneous group of neurodevelopmental diseases representing a severe burden to affected individuals and their caretakers. Despite substantial improvement towards understanding of ASD etiology and pathogenesis, as well as increased social awareness and more intensive research, no effective drugs have been successfully developed to resolve the main and most cumbersome ASD symptoms. Hence, finding better treatments, which may act as “disease-modifying” agents, and novel biomarkers for earlier ASD diagnosis and disease stage determination are needed. Diverse mutations of core components and consequent malfunctions of several cell signaling pathways have already been found in ASD by a series of experimental platforms, including genetic associations analyses and studies utilizing pre-clinical animal models and patient samples. These signaling cascades govern a broad range of neurological features such as neuronal development, neurotransmission, metabolism, and homeostasis, as well as immune regulation and inflammation. Here, we review the current knowledge on signaling pathways which are commonly disrupted in ASD and autism-related conditions. As such, we further propose ways to translate these findings into the development of genetic and biochemical clinical tests for early autism detection. Moreover, we highlight some putative druggable targets along these pathways, which, upon further research efforts, may evolve into novel therapeutic interventions for certain ASD conditions. Lastly, we also refer to the crosstalk among these major signaling cascades as well as their putative implications in therapeutics. Based on this collective information, we believe that a timely and accurate modulation of these prominent pathways may shape the neurodevelopment and neuro-immune regulation of homeostatic patterns and, hopefully, rescue some (if not all) ASD phenotypes.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Abbreviations

β-TrCP:

Beta-transducin repeat-containing protein

ADH:

Alcohol dehydrogenase

AKT:

Protein kinase B (PKB)

ALDH:

Retinaldehyde dehydrogenase

ALDH1A2:

ALDH isoform 1A2

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

ASD:

Autism spectrum disorder

APC:

Adenomatous polyposis coli

ATP:

Adenosine triphosphate

BCL2:

B-cell CLL/lymphoma 2 apoptosis regulator

BCL9:

B-cell CLL/lymphoma 9 transcription co-activator

BDNF:

Brain-derived neurotrophic factor

BMP:

Bone morphogenetic protein

BRAF :

Proto-oncogene B-Raf encoding gene

CBP:

CREB(cAMP response element)-binding protein

CDC:

Centers for Disease Control and Prevention (USA)

CDH7/8/9:

Chromodomain helicase DNA binding protein 7/8/9

CEP290:

Centrosomal protein of 290 kDa

CK1α:

Casein kinase 1α

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

CTNF:

Ciliary neurotrophic factor

CTNNB1 :

Catenin beta 1 gene (β-catenin gene)

Cyp26:

Cytochrome P450 enzyme family 26

Dhh:

Desert Hedgehog

DISC1:

Disrupted in schizophrenia 1

DNMT:

DNA methyltransferase

DKK:

Dickkopf

DSM-5:

Diagnostic and statistical manual of mental disorders 5th edition

Dvl:

Disheveled

DYRK1B:

Dual specificity tyrosine phosphorylation regulated kinase 1B

EIF4E :

Eukaryotic translation initiation factor 4E gene

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

EPHA7 :

Ephrin type-A receptor 7 gene

ERK/MAPK/MEK:

Mitogen-activated protein kinase

FDA:

Food and Drug Administration

FMRP:

Fragile X mental retardation protein

FXS:

Fragile X syndrome

FZD:

Frizzled (family of G protein-coupled receptors)

GABA:

Gamma-amino butyric acid

GDF:

Growth and differentiation factor

Gli:

Glioma-associated oncogene/transcription factor

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

Grb2:

Growth factor receptor-bound protein

GSK-3β:

Glycogen synthase kinase 3β

Hh:

Hedgehog

HOX:

Homeobox

HRAS :

HRas GTPase gene

HTR2C :

Hydroxytryptamine (serotonin) receptor (human, X chromosomal) gene

IκB:

Inhibitor of nuclear factor kappa-B

I-SMADs:

Inhibitory SMADs

IGF-1:

Insulin-like growth factor 1

IFN-γ:

Interferon gamma

IL:

Interleukin

Ihh:

Indian Hedgehog

IKKα:

IκB kinase alpha

IKKβ:

IκB kinase beta

IKKγ:

IκB kinase gamma

iNOS:

Inducible nitric oxide synthase

iPSC:

Induced pluripotent stem cell

JAK:

Janus kinase

KRAS:

Kirsten rat sarcoma viral oncogene homolog

LEF:

Lymphoid enhancer factor

LOF:

Loss of function

LRP5/6:

Lipoprotein receptor-related protein 5/6

MeCP2:

Methyl-CpG-binding protein 2

MEK1/2 :

Mitogen-activated protein kinase 1 or 2 gene

mTOR:

Mammalian target of rapamycin

mTORC1:

MTOR Complex 1

mTORC2:

MTOR Complex 2

NFI:

Neurofibromatosis Type I

NF-κB:

Nuclear factor kappa B

NIK:

NF-κB inducing kinase

NMDA:

N-Methyl-d-aspartate

NPC:

Neural precursor/progenitor cell

p300:

E1A binding protein p300, transcription co-activator

Ptch1:

Patched 1

PCDH20 :

Protocadherin-20 gene

PI3K:

Phosphoinositide 3-kinase

PIP2:

Phosphatidylinositol 4,5-bisphosphate

PIP3:

Phosphatidylinositol 3,4,5-bisphosphate

PKC:

Protein kinase C

PTEN:

Phosphatase and tensin homolog

RA:

Retinoic acid

RAI1:

Retinoic acid inducible

RAR:

Retinoic acid receptor

RARE:

Retinoic acid response element

RAS:

Rat sarcoma viral oncogene homolog

RAF1 :

RAF proto-oncogene serine/threonine-protein kinase gene

RDH:

Retinol dehydrogenases

RelA:

Nuclear factor NF-kappa B p65 subunit

RelB:

RELB proto-oncogene, NF-κB Subunit

RERE :

Arginine-glutamic acid dipeptide repeats

RERE:

Arginine-glutamic acid dipeptide repeats encoded nuclear receptor coregulator

RHD:

Rel homology domain

RHEB:

Ras homolog enriched in brain

ROR:

Retinoic acid-related orphan receptors

RORA :

Retinoic acid-related orphan receptor α gene

RORE:

ROR response elements

R-SMADs:

Receptor-regulated SMADs

RXR:

Retinoid X receptor

S6K:

Ribosomal protein S6 kinase

SEMA3A :

Semaphorin-3A gene

SFARI:

Simons foundation autism research initiative

SFRP:

Secreted frizzled-related proteins

SGK1:

Serine/threonine-protein kinase

Shh:

Sonic Hedgehog

SLOS:

Smith-Lemli-Opitz syndrome

SMO:

Smoothened

SNP:

Single-nucleotide polymorphism

SOS:

Son of sevenless

SOCS:

Suppressors of cytokine signaling proteins

SSRI:

Selective serotonin reuptake inhibitor

STAT:

Signal transducer and activator of transcription

SuFu:

Suppressor of fused

TAK1:

Mitogen-activated protein kinase 7 (MAP3K7)

TCF:

T-cell factor

TET:

Ten eleven translocation

TF:

Transcription factor

Th:

T-helper cell

TGF-β:

Transforming growth factor beta

TGFBR1:

Type 1 TGF-β receptor

TGFBR2:

Type 2 TGF-β receptor

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TNFR:

Tumor necrosis factors receptors

Treg:

Regulatory T-cell

TSC1/2:

Tuberous sclerosis complex 1 or 2

Tyk2:

Tyrosine kinase 2

UBE3A:

Ubiquitin-protein Ligase E3 = E6AP ubiquitin-protein ligase

VA:

Valproic acid

Wnt:

Wingless-type/Int-1 (known as: INT1 and related gene products)

WIF:

Wnt inhibiting factor

References

  1. Adler BA, Wink LK, Early M et al (2015) Drug-refractory aggression, self-injurious behavior, and severe tantrums in autism spectrum disorders: a chart review study. Autism 19:102–106. https://doi.org/10.1177/1362361314524641

    Article  PubMed  Google Scholar 

  2. Ahmad SF, Nadeem A, Ansari MA et al (2017a) Upregulation of IL-9 and JAK-STAT signaling pathway in children with autism. Prog Neuropsychopharmacol Biol Psychiatry 79:472–480. https://doi.org/10.1016/j.pnpbp.2017.08.002

    CAS  Article  PubMed  Google Scholar 

  3. Ahmad SF, Zoheir KMA, Ansari MA et al (2017b) Dysregulation of Th1, Th2, Th17, and T regulatory cell-related transcription factor signaling in children with autism. Mol Neurobiol 54:4390–4400. https://doi.org/10.1007/s12035-016-9977-0

    CAS  Article  PubMed  Google Scholar 

  4. Ahmad SF, Ansari MA, Nadeem A et al (2018) Resveratrol attenuates pro-inflammatory cytokines and activation of JAK1-STAT3 in BTBR T(+) Itpr3(tf)/J autistic mice. Eur J Pharmacol 829:70–78. https://doi.org/10.1016/j.ejphar.2018.04.008

    CAS  Article  PubMed  Google Scholar 

  5. Ahmad SF, Ansari MA, Nadeem A et al (2020) Inhibition of tyrosine kinase signaling by tyrphostin AG126 downregulates the IL-21/IL-21R and JAK/STAT pathway in the BTBR mouse model of autism. Neurotoxicology 77:1–11. https://doi.org/10.1016/j.neuro.2019.12.003

    CAS  Article  PubMed  Google Scholar 

  6. Al-Ayadhi LY (2012) Relationship between sonic hedgehog protein, brain-derived neurotrophic factor and oxidative stress in autism spectrum disorders. Neurochem Res 37:394–400. https://doi.org/10.1007/s11064-011-0624-x

    CAS  Article  PubMed  Google Scholar 

  7. Al-Ayadhi L, Alhowikan AM, Halepoto DM (2018) Impact of auditory integrative training on transforming growth factor-beta1 and its effect on behavioral and social emotions in children with autism spectrum disorder. Med Princ Pract 27:23–29. https://doi.org/10.1159/000486572

    Article  PubMed  PubMed Central  Google Scholar 

  8. Alvarez-Buylla A, Ihrie RA (2014) Sonic hedgehog signaling in the postnatal brain. Semin Cell Dev Biol 33:105–111. https://doi.org/10.1016/j.semcdb.2014.05.008

    CAS  Article  PubMed  Google Scholar 

  9. American Psychiatric Publishing (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Publishing, New York

    Google Scholar 

  10. Aoki CA, Borchers AT, Li M et al (2005) Transforming growth factor beta (TGF-beta) and autoimmunity. Autoimmunol Rev 4:450–459. https://doi.org/10.1016/j.autrev.2005.03.006

    CAS  Article  Google Scholar 

  11. Ashwood P, Enstrom A, Krakowiak P et al (2008) Decreased transforming growth factor beta1 in autism: a potential link between immune dysregulation and impairment in clinical behavioral outcomes. J Neuroimmunol 204:149–153. https://doi.org/10.1016/j.jneuroim.2008.07.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Ashwood P, Krakowiak P, Hertz-Picciotto I et al (2011) Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immunol 25:40–45. https://doi.org/10.1016/j.bbi.2010.08.003

    CAS  Article  Google Scholar 

  13. Baio J, Wiggins L, Christensen DL et al (2018) Prevalence of Autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2014. MMWR Surveill Summ 67:1–23. https://doi.org/10.15585/mmwr.ss6706a1

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bashir S, Halepoto DM, Al-Ayadhi L (2014) Serum level of desert hedgehog protein in autism spectrum disorder: preliminary results. Med Princ Pract 23:14–17. https://doi.org/10.1159/000354295

    Article  PubMed  Google Scholar 

  15. Belgacem YH, Hamilton AM, Shim S et al (2016) The many hats of sonic hedgehog signaling in nervous system development and disease. J Dev Biol. https://doi.org/10.3390/jdb4040035

    Article  PubMed  PubMed Central  Google Scholar 

  16. Benitez-Burraco A, Lattanzi W, Murphy E (2016) Language impairments in ASD resulting from a failed domestication of the human brain. Front Neurosci 10:373. https://doi.org/10.3389/fnins.2016.00373

    Article  PubMed  PubMed Central  Google Scholar 

  17. Besedovsky HO, del Rey A, Klusman I et al (1991) Cytokines as modulators of the hypothalamus-pituitary-adrenal axis. J Steroid Biochem Mol Biol 40:613–618. https://doi.org/10.1016/0960-0760(91)90284-c

    CAS  Article  PubMed  Google Scholar 

  18. Biever A, Valjent E, Puighermanal E (2015) Ribosomal protein S6 phosphorylation in the nervous system: From regulation to function. Front Mol Neurosci 8:75. https://doi.org/10.3389/fnmol.2015.00075

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Bilder DA, Bakian AV, Stevenson DA et al (2016) Brief report: the prevalence of neurofibromatosis type 1 among children with autism spectrum disorder identified by the autism and developmental disabilities monitoring network. J Autism Dev Disord 46:3369–3376. https://doi.org/10.1007/s10803-016-2877-3

    Article  PubMed  PubMed Central  Google Scholar 

  20. Blassberg R, Macrae JI, Briscoe J, Jacob J (2016) Reduced cholesterol levels impair smoothened activation in Smith-Lemli-Opitz syndrome. Hum Mol Genet 25:693–705. https://doi.org/10.1093/hmg/ddv507

    CAS  Article  PubMed  Google Scholar 

  21. Boland MR, Tatonetti NP (2016) Investigation of 7-dehydrocholesterol reductase pathway to elucidate off-target prenatal effects of pharmaceuticals: a systematic review. Pharmacogenomics J 16:411–429. https://doi.org/10.1038/tpj.2016.48

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Boyle SC, Kim M, Valerius MT et al (2011) Notch pathway activation can replace the requirement for Wnt4 and wnt9b in mesenchymal-to-epithelial transition of nephron stem cells. Development 138:4245–4254. https://doi.org/10.1242/dev.070433

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Bozdagi O, Tavassoli T, Buxbaum JD (2013) Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay. Mol Autism 4:9. https://doi.org/10.1186/2040-2392-4-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Bozzi Y, Provenzano G, Casarosa S (2018) Neurobiological bases of autism–epilepsy comorbidity: a focus on excitation/inhibition imbalance. Eur J Neurosci 47:534–548. https://doi.org/10.1111/ejn.13595

    Article  PubMed  Google Scholar 

  25. Breder CD, Dinarello CA, Saper CB (1988) Interleukin-1 immunoreactive innervation of the human hypothalamus. Science 240:321–324. https://doi.org/10.1126/science.3258444

    CAS  Article  PubMed  Google Scholar 

  26. Caban C, Khan N, Hasbani D, Crino PB (2016) Genetics of tuberous sclerosis complex: implications for clinical practice. Appl Clin Genet 10:1–8. https://doi.org/10.2147/TACG.S90262

    Article  PubMed  PubMed Central  Google Scholar 

  27. Carballo GB, Honorato JR, de Lopes GPF, de Spohr TCL (2018) A highlight on sonic hedgehog pathway. Cell Commun Signal 16:11. https://doi.org/10.1186/s12964-018-0220-7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Cargnello M, Roux PP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75:50–83. https://doi.org/10.1128/MMBR.00031-10

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Cataldo I, Azhari A, Esposito G (2018) A review of oxytocin and arginine-vasopressin receptors and their modulation of autism spectrum disorder. Front Mol Neurosci 11:27. https://doi.org/10.3389/fnmol.2018.00027

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Chatterjee S, Sil PC (2019) Targeting the crosstalks of Wnt pathway with Hedgehog and Notch for cancer therapy. Pharmacol Res 142:251–261. https://doi.org/10.1016/j.phrs.2019.02.027

    CAS  Article  PubMed  Google Scholar 

  31. Chen L, Tao Y, Song F et al (2016) Evidence for genetic regulation of mRNA expression of the dosage-sensitive gene retinoic acid induced-1 (RAI1) in human brain. Sci Rep 6:19010. https://doi.org/10.1038/srep19010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Cheng B, Zhu J, Yang T et al (2020) Vitamin A deficiency increases the risk of gastrointestinal comorbidity and exacerbates core symptoms in children with autism spectrum disorder. Pediatr Res. https://doi.org/10.1038/s41390-020-0865-y

    Article  PubMed  Google Scholar 

  33. Chenn A, Walsh CA (2002) Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297:365–369. https://doi.org/10.1126/science.1074192

    CAS  Article  PubMed  Google Scholar 

  34. Choi GB, Yim YS, Wong H et al (2016) The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351:933–939. https://doi.org/10.1126/science.aad0314

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Chopko TC, Lindsley CW (2018) Classics in chemical neuroscience: risperidone. ACS Chem Neurosci 9:1520–1529. https://doi.org/10.1021/acschemneuro.8b00159

    CAS  Article  PubMed  Google Scholar 

  36. Clapcote SJ, Lipina TV, Millar JK et al (2007) Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54:387–402. https://doi.org/10.1016/j.neuron.2007.04.015

    CAS  Article  PubMed  Google Scholar 

  37. Clevers H, Nusse R (2012) Wnt/β-catenin signaling and disease. Cell 149:1192–1205. https://doi.org/10.1016/j.cell.2012.05.012

    CAS  Article  PubMed  Google Scholar 

  38. Coghlan S, Horder J, Inkster B et al (2012) GABA system dysfunction in autism and related disorders: from synapse to symptoms. Neurosci Biobehav Rev 36:2044–2055. https://doi.org/10.1016/j.neubiorev.2012.07.005

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Correa RG, Tergaonkar V, Ng JK et al (2004) Characterization of NF-kappa B/I kappa B proteins in zebra fish and their involvement in notochord development. Mol Cell Biol 24:5257–5268. https://doi.org/10.1128/MCB.24.12.5257-5268.2004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Croen LA, Grether JK, Yoshida CK et al (2011) Antidepressant use during pregnancy and childhood autism spectrum disorders. Arch Gen Psychiatry 68:1104–1112. https://doi.org/10.1001/archgenpsychiatry.2011.73

    Article  PubMed  Google Scholar 

  41. Cukier HN, Dueker ND, Slifer SH et al (2014) Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders. Mol Autism 5:1. https://doi.org/10.1186/2040-2392-5-1

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Dawson G, Jones EJH, Merkle K et al (2012) Early behavioral intervention is associated with normalized brain activity in young children with autism. J Am Acad Child Adolesc Psychiatry 51:1150–1159. https://doi.org/10.1016/j.jaac.2012.08.018

    Article  PubMed  PubMed Central  Google Scholar 

  43. de la Torre-Ubieta L, Won H, Stein JL, Geschwind DH (2016) Advancing the understanding of autism disease mechanisms through genetics. Nat Med 22:345–361. https://doi.org/10.1038/nm.4071

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. del Rey A, Besedovsky HO, Sorkin E et al (1981) Immunoregulation mediated by the sympathetic nervous system, II. Cell Immunol 63:329–334. https://doi.org/10.1016/0008-8749(81)90012-5

    Article  PubMed  Google Scholar 

  45. Delbroek H, Steyaert J, Legius E (2011) An 8.9 year old girl with autism and Gorlin syndrome. Eur J Paediatr Neurol 15:268–270. https://doi.org/10.1016/j.ejpn.2010.12.001

    Article  PubMed  Google Scholar 

  46. Deverman BE, Patterson PH (2009) Cytokines and CNS development. Neuron 64:61–78. https://doi.org/10.1016/j.neuron.2009.09.002

    CAS  Article  PubMed  Google Scholar 

  47. DiCarlo GE, Aguilar JI, Matthies HJ et al (2019) Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors. J Clin Investig 129:3407–3419. https://doi.org/10.1172/JCI127411

    Article  PubMed  Google Scholar 

  48. Dong F, Jiang J, McSweeney C et al (2016) Deletion of CTNNB1 in inhibitory circuitry contributes to autism-associated behavioral defects. Hum Mol Genet 25:2738–2751. https://doi.org/10.1093/hmg/ddw131

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Durak O, Gao F, Kaeser-Woo YJ et al (2016) Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling. Nat Neurosci 19:1477–1488. https://doi.org/10.1038/nn.4400

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Ehninger D, Han S, Shilyansky C et al (2008) Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nat Med 14:843–848. https://doi.org/10.1038/nm1788

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. Eissa N, Al-Houqani M, Sadeq A et al (2018) Current enlightenment about etiology and pharmacological treatment of autism spectrum disorder. Front Neurosci. https://doi.org/10.3389/fnins.2018.00304

    Article  PubMed  PubMed Central  Google Scholar 

  52. El Gohary TM, El Aziz NA, Darweesh M, Sadaa ES (2015) Plasma level of transforming growth factor β 1 in children with autism spectrum disorder. Egypt J Ear, Nose, Throat Allied Sci 16:69–73. https://doi.org/10.1016/j.ejenta.2014.12.002

    Article  Google Scholar 

  53. El Hokayem J, Weeber E, Nawaz Z (2018) Loss of Angelman syndrome protein E6AP disrupts a novel antagonistic estrogen-retinoic acid transcriptional crosstalk in neurons. Mol Neurobiol 55:7187–7200. https://doi.org/10.1007/s12035-018-0871-9

    CAS  Article  PubMed  Google Scholar 

  54. El-Ansary A, Al-Ayadhi L (2012) Neuroinflammation in autism spectrum disorders. J Neuroinflamm 9:265. https://doi.org/10.1186/1742-2094-9-265

    CAS  Article  Google Scholar 

  55. Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES (2000) The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52:595–638

    CAS  PubMed  Google Scholar 

  56. Ellis H, Ma CX (2019) PI3K inhibitors in breast cancer therapy. Curr Oncol Rep 12:342

    Google Scholar 

  57. Emanuele E, Orsi P, Boso M et al (2010) Low-grade endotoxemia in patients with severe autism. Neurosci Lett 471:162–165. https://doi.org/10.1016/j.neulet.2010.01.033

    CAS  Article  PubMed  Google Scholar 

  58. Enstrom AM, Onore CE, Water JA, Ashwood P (2010) Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain Behav Immunol 24:64–71. https://doi.org/10.1016/j.bbi.2009.08.001

    CAS  Article  Google Scholar 

  59. Fakhoury M (2015) Autistic spectrum disorders: a review of clinical features, theories and diagnosis. Int J Dev Neurosci 43:70–77. https://doi.org/10.1016/j.ijdevneu.2015.04.003

    Article  PubMed  Google Scholar 

  60. Fang WQ, Chen WW, Jiang L et al (2014) Overproduction of upper-layer neurons in the neocortex leads to autism-like features in mice. Cell Rep 9:1635–1643. https://doi.org/10.1016/j.celrep.2014.11.003

    CAS  Article  PubMed  Google Scholar 

  61. Faravelli I, Bucchia M, Rinchetti P et al (2014) Motor neuron derivation from human embryonic and induced pluripotent stem cells: experimental approaches and clinical perspectives. Stem Cell Res Ther 5:87. https://doi.org/10.1186/scrt476

    Article  PubMed  PubMed Central  Google Scholar 

  62. Faridar A, Jones-Davis D, Rider E et al (2014) Mapk/Erk activation in an animal model of social deficits shows a possible link to autism. Mol Autism 5:57. https://doi.org/10.1186/2040-2392-5-57

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. Farmer C, Thurm A, Grant P (2013) Pharmacotherapy for the core symptoms in autistic disorder: current status of the research. Drugs 73:303–314. https://doi.org/10.1007/s40265-013-0021-7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. Fatemi SH, Halt AR, Stary JM et al (2002) Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry 52:805–810. https://doi.org/10.1016/s0006-3223(02)01430-0

    CAS  Article  PubMed  Google Scholar 

  65. Fragoso YD, Stoney PN, Shearer KD et al (2015) Expression in the human brain of retinoic acid induced 1, a protein associated with neurobehavioural disorders. Brain Struct Funct 220:1195–1203. https://doi.org/10.1007/s00429-014-0712-1

    CAS  Article  PubMed  Google Scholar 

  66. Fraser MM, Bayazitov IT, Zakharenko SS, Baker SJ (2008) Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities. Neuroscience 151:476–488. https://doi.org/10.1016/j.neuroscience.2007.10.048

    CAS  Article  PubMed  Google Scholar 

  67. Fregeau B, Kim BJ, Hernandez-Garcia A et al (2016) De novo mutations of RERE cause a genetic syndrome with features that overlap those associated with proximal 1p36 deletions. Am J Hum Genet 98:963–970. https://doi.org/10.1016/j.ajhg.2016.03.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Fuccillo M, Joyner AL, Fishell G (2006) Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development. Nat Rev Neurosci 7:772–783. https://doi.org/10.1038/nrn1990

    CAS  Article  PubMed  Google Scholar 

  69. Funamoto S, Meili R, Lee S et al (2002) Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis. Cell 109:611–623. https://doi.org/10.1016/S0092-8674(02)00755-9

    CAS  Article  PubMed  Google Scholar 

  70. Furmanski AL, Saldana JI, Ono M et al (2013) Tissue-derived hedgehog proteins modulate Th differentiation and disease. J Immunol 190:2641–2649. https://doi.org/10.4049/jimmunol.1202541

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. Garg S, Brooks A, Burns A et al (2017) Autism spectrum disorder and other neurobehavioural comorbidities in rare disorders of the Ras/MAPK pathway. Dev Med Child Neurol 59:544–549. https://doi.org/10.1111/dmcn.13394

    Article  PubMed  Google Scholar 

  72. Ghanizadeh A (2012) Malondialdehyde, Bcl-2, superoxide dismutase and glutathione peroxidase may mediate the association of sonic hedgehog protein and oxidative stress in autism. Neurochem Res 37:899–901. https://doi.org/10.1007/s11064-011-0667-z

    CAS  Article  PubMed  Google Scholar 

  73. Ghyselinck NB, Duester G (2019) Retinoic acid signaling pathways. Development 146:167502. https://doi.org/10.1242/dev.167502

    CAS  Article  Google Scholar 

  74. Giaccone G, Bazhenova LA, Nemunaitis J et al (2015) A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer. Eur J Cancer 51:2321–2329. https://doi.org/10.1016/j.ejca.2015.07.035

    CAS  Article  PubMed  Google Scholar 

  75. Goines PE, Croen LA, Braunschweig D et al (2011) Increased midgestational IFN-gamma, IL-4 and IL-5 in women bearing a child with autism: a case-control study. Mol Autism 2:13. https://doi.org/10.1186/2040-2392-2-13

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. Goldani AAS, Downs SR, Widjaja F et al (2014) Biomarkers in autism. Front Psychiatry 5:100. https://doi.org/10.3389/fpsyt.2014.00100

    Article  PubMed  PubMed Central  Google Scholar 

  77. Gottfried C, Bambini-Junior V, Francis F et al (2015) The impact of neuroimmune alterations in autism spectrum disorder. Front Psychiatry 6:121. https://doi.org/10.3389/fpsyt.2015.00121

    Article  PubMed  PubMed Central  Google Scholar 

  78. Greenblatt EJ, Spradling AC (2018) Fragile X mental retardation 1 gene enhances the translation of large autism-related proteins. Science 361:709–712. https://doi.org/10.1126/science.aas9963

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. Guo M, Zhu J, Yang T et al (2018) Vitamin A improves the symptoms of autism spectrum disorders and decreases 5-hydroxytryptamine (5-HT): a pilot study. Brain Res Bull 137:35–40. https://doi.org/10.1016/j.brainresbull.2017.11.001

    CAS  Article  PubMed  Google Scholar 

  80. Guo M, Zhu J, Yang T et al (2019) Vitamin A and vitamin D deficiencies exacerbate symptoms in children with autism spectrum disorders. Nutr Neurosci 22:637–647. https://doi.org/10.1080/1028415X.2017.1423268

    CAS  Article  PubMed  Google Scholar 

  81. Halepoto DM, Bashir S, Zeina R, Al-Ayadhi LY (2015) Correlation between hedgehog (Hh) PROTEIN family and brain-derived neurotrophic factor (BDNF) in autism spectrum disorder (ASD). J Coll Phys Surg Pak 25:882–885

    Google Scholar 

  82. Hayward P, Kalmar T, Arias AM (2008) Wnt/Notch signalling and information processing during development. Development 135:411–424. https://doi.org/10.1242/dev.000505

    CAS  Article  PubMed  Google Scholar 

  83. Hellings JA, Arnold LE, Han JC (2017) Dopamine antagonists for treatment resistance in autism spectrum disorders: review and focus on BDNF stimulators loxapine and amitriptyline. Expert Opin Pharmacother 18:581–588. https://doi.org/10.1080/14656566.2017.1308483

    CAS  Article  PubMed  Google Scholar 

  84. Hill SA, Blaeser AS, Coley AA et al (2019) Sonic hedgehog signaling in astrocytes mediates cell type-specific synaptic organization. Elife. https://doi.org/10.7554/eLife.45545

    Article  PubMed  PubMed Central  Google Scholar 

  85. Hirsch MM, Deckmann I, Santos-Terra J et al (2020) Effects of single-dose antipurinergic therapy on behavioral and molecular alterations in the valproic acid-induced animal model of autism. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2019.107930

    Article  PubMed  Google Scholar 

  86. Hormozdiari F, Penn O, Borenstein E, Eichler EE (2015) The discovery of integrated gene networks for autism and related disorders. Genome Res. https://doi.org/10.1101/gr.178855.114.142

    Article  PubMed  PubMed Central  Google Scholar 

  87. Hu Y, Chen W, Wu L et al (2019) TGF-β1 restores hippocampal synaptic plasticity and memory in Alzheimer model via the PI3K/Akt/Wnt/β-catenin signaling pathway. J Mol Neurosci 67:142–149. https://doi.org/10.1007/s12031-018-1219-7

    CAS  Article  PubMed  Google Scholar 

  88. Huang W-H, Guenthner CJ, Xu J et al (2016) Molecular and neural functions of Rai1, the causal gene for smith-magenis syndrome. Neuron 92:392–406. https://doi.org/10.1016/j.neuron.2016.09.019

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. Ikeda H, Hideshima T, Fulciniti M et al (2010) PI3K/p110δ is a novel therapeutic target in multiple myeloma. Blood 116:1460–1468. https://doi.org/10.1182/blood-2009-06-222943

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. Inoki K, Li Y, Zhu T et al (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4:648–657. https://doi.org/10.1038/ncb839

    CAS  Article  PubMed  Google Scholar 

  91. Jaramillo TC, Speed HE, Xuan Z et al (2017) Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function. Autism Res 10:42–65. https://doi.org/10.1002/aur.1664

    Article  PubMed  Google Scholar 

  92. Jyonouchi H, Sun S, Le H (2001) Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol 120:170–179. https://doi.org/10.1016/s0165-5728(01)00421-0

    CAS  Article  PubMed  Google Scholar 

  93. Kahn M (2014) Can we safely target the WNT pathway? Nat Rev Drug Discov 13:513–532. https://doi.org/10.1038/nrd4233

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. Kalkman HO (2012) A review of the evidence for the canonical Wnt pathway in autism spectrum disorders. Mol Autism 3:1–12. https://doi.org/10.1186/2040-2392-3-10

    CAS  Article  Google Scholar 

  95. Kaminska B, Gozdz A, Zawadzka M et al (2009) MAPK signal transduction underlying brain inflammation and gliosis as therapeutic target. Anat Rec (Hoboken) 292:1902–1913. https://doi.org/10.1002/ar.21047

    CAS  Article  Google Scholar 

  96. Karunaweera N, Raju R, Gyengesi E, Münch G (2015) Plant polyphenols as inhibitors of NF-κB induced cytokine production—a potential anti-inflammatory treatment for Alzheimer’s disease? Front Mol Neurosci 8:24

    Article  Google Scholar 

  97. Kashima R, Hata A (2018) The role of TGF-beta superfamily signaling in neurological disorders. Acta Biochim Biophys Sin (Shanghai) 50:106–120. https://doi.org/10.1093/abbs/gmx124

    CAS  Article  Google Scholar 

  98. Katoh Y, Katoh M (2009) Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. Curr Mol Med 9:873–886. https://doi.org/10.2174/156652409789105570

    CAS  Article  PubMed  Google Scholar 

  99. Kaur N, Lu B, Monroe RK et al (2005) Inducers of oxidative stress block ciliary neurotrophic factor activation of Jak/STAT signaling in neurons. J Neurochem 92:1521–1530. https://doi.org/10.1111/j.1471-4159.2004.02990.x

    CAS  Article  PubMed  Google Scholar 

  100. Kawashima N, Nakayama K, Itoh K et al (2010) Reversible dimerization of EGFR revealed by single-molecule fluorescence imaging using quantum dots. Chem A Eur J 16:1186–1192. https://doi.org/10.1002/chem.200902963

    CAS  Article  Google Scholar 

  101. Kerbeshian J, Burd L, Avery K (2001) Pharmacotherapy of autism: a review and clinical approach. J Dev Phys Disabil 13:199–228. https://doi.org/10.1023/A:1016686802786

    Article  Google Scholar 

  102. Kern JK, Geier DA, King PG et al (2015) Shared brain connectivity issues, symptoms, and comorbidities in autism spectrum disorder, attention deficit/hyperactivity disorder, and tourette syndrome. Brain Connect 5:321–335. https://doi.org/10.1089/brain.2014.0324

    Article  PubMed  Google Scholar 

  103. Kern JK, Geier DA, Sykes LK, Geier MR (2016) Relevance of neuroinflammation and encephalitis in autism. Front Cell Neurosci 9:519. https://doi.org/10.3389/fncel.2015.00519

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. Khakzad MR, Salari F, Javanbakht M et al (2015) Transforming growth factor beta 1 869T/C and 915G/C polymorphisms and risk of autism spectrum disorders. Rep Biochem Mol Biol 3:82–88

    PubMed  PubMed Central  Google Scholar 

  105. Khatri N, Man H-Y (2019) The autism and angelman syndrome protein Ube3A/E6AP: the gene, E3 ligase ubiquitination targets and neurobiological functions. Front Mol Neurosci 12:109

    CAS  Article  Google Scholar 

  106. Khaw P, Grehn F, Holló G et al (2007) A phase III study of subconjunctival human anti-transforming growth factor beta(2) monoclonal antibody (CAT-152) to prevent scarring after first-time trabeculectomy. Ophthalmology 114:1822–1830. https://doi.org/10.1016/j.ophtha.2007.03.050

    Article  PubMed  Google Scholar 

  107. Kilander MBC, Wang C-H, Chang C-H et al (2018) A rare human CEP290 variant disrupts the molecular integrity of the primary cilium and impairs Sonic Hedgehog machinery. Sci Rep 8:17335. https://doi.org/10.1038/s41598-018-35614-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. Klaus A, Birchmeier W (2008) WNT signalling and its impact on development and cancer. Nat Rev Cancer 8:387

    CAS  Article  Google Scholar 

  109. Klein SD, Nguyen DC, Bhakta V et al (2019) Mutations in the sonic hedgehog pathway cause macrocephaly-associated conditions due to crosstalk to the PI3K/AKT/mTOR pathway. Am J Med Genet A 179:2517–2531. https://doi.org/10.1002/ajmg.a.61368

    CAS  Article  PubMed  Google Scholar 

  110. Kolevzon A, Bush L, Wang AT et al (2014) A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome. Mol Autism 5:54. https://doi.org/10.1186/2040-2392-5-54

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. Komiya Y, Habas R (2008) Wnt signal transduction pathways. Organogenesis 4:68–75. https://doi.org/10.4161/org.4.2.5851

    Article  PubMed  PubMed Central  Google Scholar 

  112. Koopmans T, Eilers R, Menzen M et al (2017) β-catenin directs nuclear factor-κB p65 output via CREB-binding protein/p300 in human airway smooth muscle. Front Immunol. https://doi.org/10.3389/fimmu.2017.01086

    Article  PubMed  PubMed Central  Google Scholar 

  113. Kumar V, Zhang M-X, Swank MW et al (2005) Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J Neurosci 25:11288–11299. https://doi.org/10.1523/JNEUROSCI.2284-05.2005

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. Kumar S, Reynolds K, Ji Y et al (2019) Impaired neurodevelopmental pathways in autism spectrum disorder: a review of signaling mechanisms and crosstalk. J Neurodev Disord 11:1–14. https://doi.org/10.1186/s11689-019-9268-y

    Article  Google Scholar 

  115. Kumawat K, Menzen MH, Bos IST et al (2013) Noncanonical WNT-5A signaling regulates TGF-β-induced extracellular matrix production by airway smooth muscle cells. FASEB J Off Publ Fed Am Soc Exp Biol 27:1631–1643. https://doi.org/10.1096/fj.12-217539

    CAS  Article  Google Scholar 

  116. Kwan V, Unda BK, Singh KK (2016) Wnt signaling networks in autism spectrum disorder and intellectual disability. J Neurodev Disord 8:1–10. https://doi.org/10.1186/s11689-016-9176-3

    Article  Google Scholar 

  117. Lai M-C, Lombardo MV, Baron-Cohen S (2014) Autism. Lancet 383:896–910. https://doi.org/10.1016/S0140-6736(13)61539-1

    Article  Google Scholar 

  118. Lai X, Wu X, Hou N et al (2018) Vitamin A deficiency induces autistic-like behaviors in rats by regulating the RARβ-CD38-oxytocin axis in the hypothalamus. Mol Nutr Food Res 62:1700754. https://doi.org/10.1002/mnfr.201700754

    CAS  Article  Google Scholar 

  119. Lawrence T (2009) The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol 1:a001651–a001651. https://doi.org/10.1101/cshperspect.a001651

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. Lee RWY, Tierney E (2011) Hypothesis: the role of sterols in autism spectrum disorder. Autism Res Treat 2011:653570. https://doi.org/10.1155/2011/653570

    Article  PubMed  PubMed Central  Google Scholar 

  121. Lee Y, Kim H, Kim J-E et al (2018) Excessive D1 dopamine receptor activation in the dorsal striatum promotes autistic-like behaviors. Mol Neurobiol 55:5658–5671. https://doi.org/10.1007/s12035-017-0770-5

    CAS  Article  PubMed  Google Scholar 

  122. Li Q, Verma IM (2002) NF-κB regulation in the immune system. Nat Rev Immunol 2:725–734. https://doi.org/10.1038/nri910

    CAS  Article  Google Scholar 

  123. Li X, Deng W, Lobo-Ruppert SM, Ruppert JM (2007) Gli1 acts through snail and E-cadherin to promote nuclear signaling by β-catenin. Oncogene 26:4489–4498. https://doi.org/10.1038/sj.onc.1210241

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. Li X, Chauhan A, Sheikh AM et al (2009) Elevated immune response in the brain of autistic patients. J Neuroimmunol 207:111–116. https://doi.org/10.1016/j.jneuroim.2008.12.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. Li M, Shin J, Risgaard RD et al (2020) Identification of FMR1-regulated molecular networks in human neurodevelopment. Genome Res 30:361–374. https://doi.org/10.1101/gr.251405.119

    Article  PubMed  Google Scholar 

  126. Liu J, Pan S, Hsieh MH et al (2013) Targeting Wnt-driven cancer through the inhibition of porcupine by LGK974. Proc Natl Acad Sci USA 110:20224–20229. https://doi.org/10.1073/pnas.1314239110

    CAS  Article  PubMed  Google Scholar 

  127. Long JM, LaPorte P, Paylor R, Wynshaw-Boris A (2004) Expanded characterization of the social interaction abnormalities in mice lacking Dvl1. Genes Brain Behav 3:51–62. https://doi.org/10.1046/j.1601-183x.2003.00045.x

    CAS  Article  PubMed  Google Scholar 

  128. Lord C, Elsabbagh M, Baird G, Veenstra-Vanderweele J (2018) Autism spectrum disorder. Lancet (London, England) 392:508–520. https://doi.org/10.1016/S0140-6736(18)31129-2

    Article  Google Scholar 

  129. Lu Z, Xu S (2006) ERK1/2 MAP kinases in cell survival and apoptosis. IUBMB Life 58:621–631. https://doi.org/10.1080/15216540600957438

    CAS  Article  PubMed  Google Scholar 

  130. Ma B, Hottiger MO (2016) Crosstalk between wnt/β-catenin and NF-κB signaling pathway during inflammation. Front Immunol. https://doi.org/10.3389/fimmu.2016.00378

    Article  PubMed  PubMed Central  Google Scholar 

  131. Madden KS, Sanders VM, Felten DL (1995) Catecholamine influences and sympathetic neural modulation of immune responsiveness. Annu Rev Pharmacol Toxicol 35:417–448. https://doi.org/10.1146/annurev.pa.35.040195.002221

    CAS  Article  PubMed  Google Scholar 

  132. Madrid LV, Mayo MW, Reuther JY, Baldwin AS (2001) Akt stimulates the transactivation potential of the RelA/p65 subunit of NF-κB through utilization of the IκB kinase and activation of the mitogen-activated protein kinase p38. J Biol Chem 276:18934–18940. https://doi.org/10.1074/jbc.M101103200

    CAS  Article  PubMed  Google Scholar 

  133. Maes M, Anderson G, Betancort Medina SR et al (2019) Integrating autism spectrum disorder pathophysiology: mitochondria, vitamin A, CD38, oxytocin, serotonin and melatonergic alterations in the placenta and gut. Curr Pharm Des 25:4405–4420. https://doi.org/10.2174/1381612825666191102165459

    CAS  Article  PubMed  Google Scholar 

  134. Maestroni GJM (2006) Sympathetic nervous system influence on the innate immune response. Ann N Y Acad Sci 1069:195–207. https://doi.org/10.1196/annals.1351.017

    Article  PubMed  Google Scholar 

  135. Magnuson B, Ekim B, Fingar DC (2011) Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J 441:1–21. https://doi.org/10.1042/BJ20110892

    CAS  Article  Google Scholar 

  136. Malek H, Ebadzadeh MM, Safabakhsh R et al (2015) Dynamics of the HPA axis and inflammatory cytokines: insights from mathematical modeling. Comput Biol Med 67:1–12. https://doi.org/10.1016/j.compbiomed.2015.09.018

    CAS  Article  PubMed  Google Scholar 

  137. Malik M, Sheikh AM, Wen G et al (2011a) Expression of inflammatory cytokines, Bcl2 and cathepsin D are altered in lymphoblasts of autistic subjects. Immunobiology 216:80–85. https://doi.org/10.1016/j.imbio.2010.03.001

    CAS  Article  PubMed  Google Scholar 

  138. Malik M, Tauqeer Z, Sheikh AM et al (2011b) NF-κB signaling in the brain of autistic subjects. Mediat Inflamm 2011:785265. https://doi.org/10.1155/2011/785265

    CAS  Article  Google Scholar 

  139. Markham A (2017) Copanlisib: first global approval. Drugs 77:2057–2062. https://doi.org/10.1007/s40265-017-0838-6

    CAS  Article  PubMed  Google Scholar 

  140. Maximo JO, Cadena EJ, Kana RK (2014) The implications of brain connectivity in the neuropsychology of autism. Neuropsychol Rev 24:16–31. https://doi.org/10.1007/s11065-014-9250-0

    Article  PubMed  PubMed Central  Google Scholar 

  141. McCubrey JA, May WS, Duronio V, Mufson A (2000) Serine/threonine phosphorylation in cytokine signal transduction. Leukemia 14:9–21. https://doi.org/10.1038/sj.leu.2401657

    CAS  Article  PubMed  Google Scholar 

  142. McDuffie A, Thurman AJ, Hagerman RJ, Abbeduto L (2015) Symptoms of autism in males with fragile X syndrome: a comparison to nonsyndromic ASD using current ADI-R scores. J Autism Dev Disord 45:1925–1937. https://doi.org/10.1007/s10803-013-2013-6

    Article  PubMed  PubMed Central  Google Scholar 

  143. Mefford H, Sharp A, Baker C et al (2008) Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med 359:1685–1699. https://doi.org/10.1056/NEJMoa0805384

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  144. Mendoza MC, Er EE, Blenis J (2011) The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci 36:320–328. https://doi.org/10.1016/j.tibs.2011.03.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  145. Mila M, Alvarez-Mora MI, Madrigal I, Rodriguez-Revenga L (2018) Fragile X syndrome: an overview and update of the FMR1 gene. Clin Genet 93:197–205. https://doi.org/10.1111/cge.13075

    CAS  Article  PubMed  Google Scholar 

  146. Moreno-Ramos OA, Olivares AM, Haider NB et al (2015) Whole-exome sequencing in a south american cohort links ALDH1A3, FOXN1 and retinoic acid regulation pathways to autism spectrum disorders. PLoS ONE 10:e0135927. https://doi.org/10.1371/journal.pone.0135927

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. Morin PJ (1999) Β-catenin signaling and cancer. BioEssays 21:1021–1030. https://doi.org/10.1002/(SICI)1521-1878(199912)22:1%3c1021:AID-BIES6%3e3.0.CO;2-P

    CAS  Article  PubMed  Google Scholar 

  148. Mousa A, Bakhiet M (2013) Role of cytokine signaling during nervous system development. Int J Mol Sci 14:13931–13957. https://doi.org/10.3390/ijms140713931

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. Nadeem A, Ahmad SF, Attia SM et al (2018) Activation of IL-17 receptor leads to increased oxidative inflammation in peripheral monocytes of autistic children. Brain Behav Immunol 67:335–344. https://doi.org/10.1016/j.bbi.2017.09.010

    CAS  Article  Google Scholar 

  150. Nagatomi R, Kaifu T, Okutsu M et al (2000) Modulation of the immune system by the autonomic nervous system and its implication in immunological changes after training. Exerc Immunol Rev 6:54–74

    CAS  PubMed  Google Scholar 

  151. Naik US, Gangadharan C, Abbagani K et al (2011) A study of nuclear transcription factor-kappa B in childhood autism. PLoS ONE 6:e19488–e19488. https://doi.org/10.1371/journal.pone.0019488

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. Neul JL (2012) The relationship of Rett syndrome and MECP2 disorders to autism. Dialog Clin Neurosci 14:253–262

    Google Scholar 

  153. Nevison C, Blaxill M, Zahorodny W (2018) California autism prevalence trends from 1931 to 2014 and comparison to national ASD data from IDEA and ADDM. J Autism Dev Disord 48:4103–4117. https://doi.org/10.1007/s10803-018-3670-2

    Article  PubMed  PubMed Central  Google Scholar 

  154. Nguyen A, Rauch TA, Pfeifer GP, Hu VW (2010) Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain. FASEB J Off Publ Fed Am Soc Exp Biol 24:3036–3051. https://doi.org/10.1096/fj.10-154484

    CAS  Article  Google Scholar 

  155. Niehrs C (2012) The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol 13:767–779. https://doi.org/10.1038/nrm3470

    CAS  Article  PubMed  Google Scholar 

  156. Nightingale S (2012) Autism spectrum disorders. Nat Rev Drug Discov 11:745–746. https://doi.org/10.1016/B978-0-12-800685-6.00016-3

    CAS  Article  PubMed  Google Scholar 

  157. Nikoletopoulou V, Sidiropoulou K, Kallergi E et al (2017) Modulation of autophagy by BDNF underlies synaptic plasticity. Cell Metab 26:230–242.e5. https://doi.org/10.1016/j.cmet.2017.06.005

    CAS  Article  PubMed  Google Scholar 

  158. Niu M, Han Y, Dy ABC et al (2017) Autism symptoms in fragile X syndrome. J Child Neurol 32:903–909. https://doi.org/10.1177/0883073817712875

    Article  PubMed  Google Scholar 

  159. Niyaz M, Khan MS, Mudassar S (2019) Hedgehog signaling: an achilles’ heel in cancer. Transl Oncol 12:1334–1344. https://doi.org/10.1016/j.tranon.2019.07.004

    Article  PubMed  PubMed Central  Google Scholar 

  160. Ohja K, Gozal E, Fahnestock M et al (2018) Neuroimmunologic and neurotrophic interactions in autism spectrum disorders: relationship to neuroinflammation. Neuromol Med 20:161–173. https://doi.org/10.1007/s12017-018-8488-8

    CAS  Article  Google Scholar 

  161. Okada K, Hashimoto K, Iwata Y et al (2007) Decreased serum levels of transforming growth factor-beta1 in patients with autism. Prog Neuropsychopharmacol Biol Psychiatry 31:187–190. https://doi.org/10.1016/j.pnpbp.2006.08.020

    CAS  Article  PubMed  Google Scholar 

  162. Okamoto H, Voleti B, Banasr M et al (2010) Wnt2 expression and signaling is increased by different classes of antidepressant treatments. Biol Psychiatry 68:521–527. https://doi.org/10.1016/j.biopsych.2010.04.023

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  163. Oztan O, Garner JP, Partap S et al (2018) Cerebrospinal fluid vasopressin and symptom severity in children with autism. Ann Neurol 84:611–615. https://doi.org/10.1002/ana.25314

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  164. Parker-Athill E, Luo D, Bailey A et al (2009) Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism. J Neuroimmunol 217:20–27. https://doi.org/10.1016/j.jneuroim.2009.08.012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  165. Patel SS, Tomar S, Sharma D et al (2017) Targeting sonic hedgehog signaling in neurological disorders. Neurosci Biobehav Rev 74:76–97. https://doi.org/10.1016/j.neubiorev.2017.01.008

    Article  PubMed  Google Scholar 

  166. Paul A, Edwards J, Pepper C, Mackay S (2018) Inhibitory-κB kinase (IKK) α and nuclear factor-κB (NFκB)-inducing kinase (NIK) as anti-cancer drug targets. Cells 7:176. https://doi.org/10.3390/cells7100176

    CAS  Article  PubMed Central  Google Scholar 

  167. Paval D (2017) A dopamine hypothesis of autism spectrum disorder. Dev Neurosci 39:355–360. https://doi.org/10.1159/000478725

    CAS  Article  PubMed  Google Scholar 

  168. Peltonen S, Kallionpaa RA, Peltonen J (2017) Neurofibromatosis type 1 (NF1) gene: beyond cafe au lait spots and dermal neurofibromas. Exp Dermatol 26:645–648. https://doi.org/10.1111/exd.13212

    CAS  Article  PubMed  Google Scholar 

  169. Pelullo M, Zema S, Nardozza F et al (2019) Wnt, Notch, and TGF-β pathways impinge on hedgehog signaling complexity: an open window on cancer. Front Genet 10:1–16. https://doi.org/10.3389/fgene.2019.00711

    CAS  Article  Google Scholar 

  170. Plata-Salaman CR, Oomura Y, Kai Y (1988) Tumor necrosis factor and interleukin-1 beta: suppression of food intake by direct action in the central nervous system. Brain Res 448:106–114. https://doi.org/10.1016/0006-8993(88)91106-7

    CAS  Article  PubMed  Google Scholar 

  171. Platt RJ, Zhou Y, Slaymaker IM et al (2017) Chd8 mutation leads to autistic-like behaviors and impaired striatal circuits. Cell Rep 19:335–350. https://doi.org/10.1016/j.celrep.2017.03.052

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  172. Porta C, Paglino C, Mosca A (2014) Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol 4:64. https://doi.org/10.3389/fonc.2014.00064

    Article  PubMed  PubMed Central  Google Scholar 

  173. Pucilowska J, Vithayathil J, Pagani M et al (2018) Pharmacological inhibition of ERK signaling rescues pathophysiology and behavioral phenotype associated with 16p11.2 chromosomal deletion in mice. J Neurosci 38:6640–6652. https://doi.org/10.1523/JNEUROSCI.0515-17.2018

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  174. Puighermanal E, Biever A, Pascoli V et al (2017) Ribosomal protein S6 phosphorylation is involved in novelty-induced locomotion, synaptic plasticity and mRNA translation. Front Mol Neurosci 10:419. https://doi.org/10.3389/fnmol.2017.00419

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  175. Purcell AE, Jeon OH, Zimmerman AW et al (2001) Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology 57:1618–1628. https://doi.org/10.1212/wnl.57.9.1618

    CAS  Article  PubMed  Google Scholar 

  176. Qiu S, Li Y, Li Y et al (2018) Association between SHANK3 polymorphisms and susceptibility to autism spectrum disorder. Gene 651:100–105. https://doi.org/10.1016/j.gene.2018.01.078

    CAS  Article  PubMed  Google Scholar 

  177. Quattrocki E, Friston K (2014) Autism, oxytocin and interoception. Neurosci Biobehav Rev 47:410–430. https://doi.org/10.1016/j.neubiorev.2014.09.012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  178. Rauen KA (2007) HRAS and the costello syndrome. Clin Genet 71:101–108. https://doi.org/10.1111/j.1399-0004.2007.00743.x

    CAS  Article  PubMed  Google Scholar 

  179. Rauen KA (2013) The RASopathies. Annu Rev Genomics Hum Genet 14:355–369. https://doi.org/10.1146/annurev-genom-091212-153523

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  180. Rhinn M, Dolle P (2012) Retinoic acid signalling during development. Development 139:843–858. https://doi.org/10.1242/dev.065938

    CAS  Article  PubMed  Google Scholar 

  181. Riobó NA, Lu K, Ai X et al (2006) Phosphoinositide 3-kinase and Akt are essential for Sonic Hedgehog signaling. Proc Natl Acad Sci USA 103:4505–4510. https://doi.org/10.1073/pnas.0504337103

    CAS  Article  PubMed  Google Scholar 

  182. Roak BJO, Vives L, Fu W et al (2012) Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 23:1619–1623

    Article  Google Scholar 

  183. Rodriguez JI, Kern JK (2011) Evidence of microglial activation in autism and its possible role in brain underconnectivity. Neuron Glia Biol 7:205–213. https://doi.org/10.1017/S1740925X12000142

    Article  PubMed  PubMed Central  Google Scholar 

  184. Rodriguez-Martinez G, Velasco I (2012) Activin and TGF-beta effects on brain development and neural stem cells. CNS Neurol Disord Drug Targets 11:844–855. https://doi.org/10.2174/1871527311201070844

    CAS  Article  PubMed  Google Scholar 

  185. Rubenstein JLR, Merzenich MM (2003) Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2:255–267. https://doi.org/10.1034/j.1601-183x.2003.00037.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  186. Russo FB, Brito A, de Freitas AM et al (2019) The use of iPSC technology for modeling autism spectrum disorders. Neurobiol Dis 130:104483. https://doi.org/10.1016/j.nbd.2019.104483

    Article  PubMed  Google Scholar 

  187. Sancheti H, Akopian G, Yin F et al (2013) Age-dependent modulation of synaptic plasticity and insulin mimetic effect of lipoic acid on a mouse model of Alzheimer’s disease. PLoS ONE 8:e69830. https://doi.org/10.1371/journal.pone.0069830

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  188. Sánchez-Alegría K, Flores-León M, Avila-Muñoz E et al (2018) PI3K signaling in neurons: a central node for the control of multiple functions. Int J Mol Sci 19:3725. https://doi.org/10.3390/ijms19123725

    CAS  Article  PubMed Central  Google Scholar 

  189. Sanders SJ, Murtha MT, Gupta AR et al (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485:237–241. https://doi.org/10.1038/nature10945

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  190. Sawicka K, Zukin RS (2012) Dysregulation of mTOR signaling in neuropsychiatric disorders: therapeutic implications. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 37:305–306. https://doi.org/10.1038/npp.2011.210

    CAS  Article  Google Scholar 

  191. Sayad A, Noroozi R, Omrani MD et al (2017) Retinoic acid-related orphan receptor alpha (RORA) variants are associated with autism spectrum disorder. Metab Brain Dis 32:1595–1601. https://doi.org/10.1007/s11011-017-0049-6

    CAS  Article  PubMed  Google Scholar 

  192. Schneider T, Przewłocki R (2005) Behavioral alterations in rats prenatally to valproic acid: animal model of autism. Neuropsychopharmacology 30:80–89. https://doi.org/10.1038/sj.npp.1300518

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  193. Senftleben U, Karin M (2002) The IKK/NF-kappaB pathway. Crit Care Med 30:S18–S26

    CAS  Article  Google Scholar 

  194. Shah RR, Bird AP (2017) MeCP2 mutations: progress towards understanding and treating Rett syndrome. Genome Med 9:17. https://doi.org/10.1186/s13073-017-0411-7

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  195. Shah S, Molinaro G, Liu B et al (2020) FMRP control of ribosome translocation promotes chromatin modifications and alternative splicing of neuronal genes linked to autism. Cell Rep 30:4459–4472.e6. https://doi.org/10.1016/j.celrep.2020.02.076

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  196. Shcheglovitov A, Shcheglovitova O, Yazawa M et al (2013) SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature 503:267–271. https://doi.org/10.1038/nature12618

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  197. Shi Z-M, Han Y-W, Han X-H et al (2016) Upstream regulators and downstream effectors of NF-kappaB in Alzheimer’s disease. J Neurol Sci 366:127–134. https://doi.org/10.1016/j.jns.2016.05.022

    CAS  Article  PubMed  Google Scholar 

  198. Sikora DM, Pettit-Kekel K, Penfield J et al (2006) The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome. Am J Med Genet A 140:1511–1518. https://doi.org/10.1002/ajmg.a.31294

    Article  PubMed  Google Scholar 

  199. Simonoff E, Pickles A, Charman T et al (2008) Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry 47:921–929. https://doi.org/10.1097/CHI.0b013e318179964f

    Article  PubMed  Google Scholar 

  200. Singh VK (1996) Plasma increase of interleukin-12 and interferon-gamma Pathological significance in autism. J Neuroimmunol 66:143–145. https://doi.org/10.1016/0165-5728(96)00014-8

    CAS  Article  PubMed  Google Scholar 

  201. Singh R, Dhanyamraju PK, Lauth M (2017) DYRK1B blocks canonical and promotes non-canonical Hedgehog signaling through activation of the mTOR/AKT pathway. Oncotarget 8:833–845. https://doi.org/10.18632/oncotarget.13662

    Article  PubMed  Google Scholar 

  202. Siveen KS, Nguyen AH, Lee JH et al (2014) Negative regulation of signal transducer and activator of transcription-3 signalling cascade by lupeol inhibits growth and induces apoptosis in hepatocellular carcinoma cells. Br J Cancer 111:1327–1337. https://doi.org/10.1038/bjc.2014.422

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  203. Sizemore N, Leung S, Stark GR (1999) Activation of phosphatidylinositol 3-Kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-κB p65/RelA subunit. Mol Cell Biol 19:4798–4805. https://doi.org/10.1128/mcb.19.7.4798

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  204. Song L, Li ZY, Liu WP, Zhao MR (2015) Crosstalk between Wnt/β-catenin and Hedgehog/Gli signaling pathways in colon cancer and implications for therapy. Cancer Biol Ther 16:1–7. https://doi.org/10.4161/15384047.2014.972215

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  205. Sousa KM, Carlos Villaescusa J, Cajanek L et al (2010) Wnt2 regulates progenitor proliferation in the developing ventral midbrain. J Biol Chem 285:7246–7253. https://doi.org/10.1074/jbc.M109.079822

    CAS  Article  PubMed  Google Scholar 

  206. Spanjer AIR, Baarsma HA, Oostenbrink LM et al (2016) TGF-β-induced profibrotic signaling is regulated in part by the WNT receptor Frizzled-8. FASEB J Off Publ Fed Am Soc Exp Biol 30:1823–1835. https://doi.org/10.1096/fj.201500129

    CAS  Article  Google Scholar 

  207. Stanton BZ, Peng LF (2010) Small-molecule modulators of the Sonic Hedgehog signaling pathway. Mol Biosyst 6:44–54. https://doi.org/10.1039/b910196a

    CAS  Article  PubMed  Google Scholar 

  208. Stefanatos GA (2008) Regression in autistic spectrum disorders. Neuropsychol Rev 18:305–319. https://doi.org/10.1007/s11065-008-9073-y

    Article  PubMed  Google Scholar 

  209. Subramanian M, Timmerman CK, Schwartz JL et al (2015) Characterizing autism spectrum disorders by key biochemical pathways. Front Neurosci 9:1–18. https://doi.org/10.3389/fnins.2015.00313

    Article  Google Scholar 

  210. Sun S-C (2017) The non-canonical NF-kappaB pathway in immunity and inflammation. Nat Rev Immunol 17:545–558. https://doi.org/10.1038/nri.2017.52

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  211. Sun J, Nan G (2017) The extracellular signal-regulated kinase 1/2 pathway in neurological diseases: a potential therapeutic target (review). Int J Mol Med 39:1338–1346. https://doi.org/10.3892/ijmm.2017.2962

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  212. Suzuki K, Matsuzaki H, Iwata K et al (2011) Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS ONE 6:e20470. https://doi.org/10.1371/journal.pone.0020470

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  213. Sweetman DU, O’Donnell SM, Lalor A et al (2019) Zinc and vitamin A deficiency in a cohort of children with autism spectrum disorder. Child Care Health Dev 45:380–386. https://doi.org/10.1111/cch.12655

    Article  PubMed  Google Scholar 

  214. Sztainberg Y, Zoghbi HY (2016) Lessons learned from studying syndromic autism spectrum disorders. Nat Neurosci 19:1408–1418. https://doi.org/10.1038/nn.4420

    CAS  Article  PubMed  Google Scholar 

  215. Tergaonkar V, Correa RG, Ikawa M, Verma IM (2005) Distinct roles of IκB proteins in regulating constitutive NF-κB activity. Nat Cell Biol 7:921–923. https://doi.org/10.1038/ncb1296

    CAS  Article  PubMed  Google Scholar 

  216. Theoharides TC, Tsilioni I, Patel AB, Doyle R (2016) Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders. Transl Psychiatry 6:e844–e844. https://doi.org/10.1038/tp.2016.77

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  217. Thomas GM, Huganir RL (2004) MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5:173–183. https://doi.org/10.1038/nrn1346

    CAS  Article  PubMed  Google Scholar 

  218. Tilot AK, Frazier TW 2nd, Eng C (2015) Balancing proliferation and connectivity in pten-associated autism spectrum disorder. Neurotherapeutics 12:609–619. https://doi.org/10.1007/s13311-015-0356-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  219. Trifonova EA, Klimenko AI, Mustafin ZS et al (2019) The mTOR signaling pathway activity and vitamin D availability control the expression of most autism predisposition genes. Int J Mol Sci. https://doi.org/10.3390/ijms20246332

    Article  PubMed  PubMed Central  Google Scholar 

  220. Tsai PT, Hull C, Chu Y et al (2012) Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488:647–651. https://doi.org/10.1038/nature11310

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  221. van der Poest CE, Jansen FE, Braun KPJ, Peters JM (2020) Update on drug management of refractory epilepsy in tuberous sclerosis complex. Pediatr Drugs 22:73–84. https://doi.org/10.1007/s40272-019-00376-0

    Article  Google Scholar 

  222. Varela-Nallar L, Inestrosa NC (2013) Wnt signaling in the regulation of adult hippocampal neurogenesis. Front Cell Neurosci 7:1–11. https://doi.org/10.3389/fncel.2013.00100

    CAS  Article  Google Scholar 

  223. Veeraragavan S, Wan Y-W, Connolly DR et al (2016) Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome. Hum Mol Genet 25:3284–3302. https://doi.org/10.1093/hmg/ddw178

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  224. Vithayathil J, Pucilowska J, Landreth GE (2018) ERK/MAPK signaling and autism spectrum disorders. Prog Brain Res 241:63–112. https://doi.org/10.1016/bs.pbr.2018.09.008

    Article  PubMed  Google Scholar 

  225. Volkmar F, Chawarska K, Klin A (2005) Autism in infancy and early childhood. Annu Rev Psychol 56:315–336. https://doi.org/10.1146/annurev.psych.56.091103.070159

    Article  PubMed  Google Scholar 

  226. Waltes R, Gfesser J, Haslinger D et al (2014) Common EIF4E variants modulate risk for autism spectrum disorders in the high-functioning range. J Neural Transm 121:1107–1116. https://doi.org/10.1007/s00702-014-1230-2

    Article  PubMed  Google Scholar 

  227. Wang Z, Xu L, Zhu X et al (2010) Demethylation of specific Wnt/β-catenin pathway genes and its upregulation in rat brain induced by prenatal valproate exposure. Anat Rec 293:1947–1953. https://doi.org/10.1002/ar.21232

    CAS  Article  Google Scholar 

  228. Wang Y, Ding Q, Yen C-J et al (2012) The crosstalk of mTOR/S6K1 and Hedgehog pathways. Cancer Cell 21:374–387. https://doi.org/10.1016/j.ccr.2011.12.028

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  229. Wang Y, Billon C, Walker JK, Burris TP (2016) Therapeutic effect of a synthetic RORalpha/gamma agonist in an animal model of autism. ACS Chem Neurosci 7:143–148. https://doi.org/10.1021/acschemneuro.5b00159

    CAS  Article  PubMed  Google Scholar 

  230. Wei H, Zou H, Sheikh AM et al (2011) IL-6 is increased in the cerebellum of autistic brain and alters neural cell adhesion, migration and synaptic formation. J Neuroinflamm 8:52. https://doi.org/10.1186/1742-2094-8-52

    CAS  Article  Google Scholar 

  231. Wen Y, Alshikho MJ, Herbert MR (2016) Pathway Network analyses for autism reveal multisystem involvement, major overlaps with other diseases and convergence upon MAPK and calcium signaling. PLoS ONE 11:e0153329. https://doi.org/10.1371/journal.pone.0153329

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  232. Wennerberg K, Rossman KL, Der CJ (2005) The Ras superfamily at a glance. J Cell Sci 118:843–846. https://doi.org/10.1242/jcs.01660

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  233. Wexler EM, Geschwind DH, Palmer TD (2008) Lithium regulates adult hippocampal progenitor development through canonical Wnt pathway activation. Mol Psychiatry 13:285–292. https://doi.org/10.1038/sj.mp.4002093

    CAS  Article  PubMed  Google Scholar 

  234. Whitmarsh AJ (2007) Regulation of gene transcription by mitogen-activated protein kinase signaling pathways. Biochim Biophys Acta Mol Cell Res 1773:1285–1298. https://doi.org/10.1016/j.bbamcr.2006.11.011

    CAS  Article  Google Scholar 

  235. Woiciechowsky C, Asadullah K, Nestler D et al (1998) Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat Med 4:808–813. https://doi.org/10.1038/nm0798-808

    CAS  Article  PubMed  Google Scholar 

  236. Wyss-Coray T, Borrow P, Brooker MJ, Mucke L (1997) Astroglial overproduction of TGF-beta 1 enhances inflammatory central nervous system disease in transgenic mice. J Neuroimmunol 77:45–50. https://doi.org/10.1016/s0165-5728(97)00049-0

    CAS  Article  PubMed  Google Scholar 

  237. Xu H, Zhuang X (2019) Atypical antipsychotics-induced metabolic syndrome and nonalcoholic fatty liver disease: a critical review. Neuropsychiatr Dis Treat 15:2087–2099. https://doi.org/10.2147/NDT.S208061

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  238. Xu N, Li X, Zhong Y (2015) Inflammatory cytokines: potential biomarkers of immunologic dysfunction in autism spectrum disorders. Mediators Inflamm 2015:531518. https://doi.org/10.1155/2015/531518

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  239. Xu Q, Liu Y-Y, Wang X et al (2018a) Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons. Mol Autism 9:65. https://doi.org/10.1186/s13229-018-0244-2

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  240. Xu X, Li C, Gao X et al (2018b) Excessive UBE3A dosage impairs retinoic acid signaling and synaptic plasticity in autism spectrum disorders. Cell Res 28:48–68. https://doi.org/10.1038/cr.2017.132

    CAS  Article  PubMed  Google Scholar 

  241. Ya W (2017) Involvement of calcium, Ras, MAPK, PI3K-Akt and mTOR signaling pathways in autism spectrum disorders. Neurol Neurother Open Access J. https://doi.org/10.23880/NNOAJ-16000110

    Article  Google Scholar 

  242. Yabut OR, Pleasure SJ (2018) Sonic Hedgehog signaling rises to the surface: emerging roles in neocortical development. Brain Plast (Amsterdam, Netherlands) 3:119–128. https://doi.org/10.3233/BPL-180064

    Article  Google Scholar 

  243. Young AMH, Campbell E, Lynch S et al (2011) Aberrant NF-kappaB expression in autism spectrum condition: a mechanism for neuroinflammation. Front Psychiatry 2:27. https://doi.org/10.3389/fpsyt.2011.00027

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  244. Yu JSL, Cui W (2016) Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development 143:3050–3060. https://doi.org/10.1242/dev.137075

    CAS  Article  PubMed  Google Scholar 

  245. Zhan T, Rindtorff N, Boutros M (2017) Wnt signaling in cancer. Oncogene 36:1461–1473. https://doi.org/10.1038/onc.2016.304

    CAS  Article  PubMed  Google Scholar 

  246. Zhang Y, Hu W (2012) NFκB signaling regulates embryonic and adult neurogenesis. Front Biol (Beijing). https://doi.org/10.1007/s11515-012-1233-z

    Article  Google Scholar 

  247. Zhang Y, Pizzute T, Pei M (2014) A review of crosstalk between MAPK and Wnt signals and its impact on cartilage regeneration. Cell Tissue Res 358:633–649. https://doi.org/10.1007/s00441-014-2010-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  248. Zhang Q, Lenardo MJ, Baltimore D (2017a) 30 years of NF-κB: a blossoming of relevance to human pathobiology. Cell 168:37–57. https://doi.org/10.1016/j.cell.2016.12.012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  249. Zhang X, He X, Li Q et al (2017b) PI3K/AKT/mTOR signaling mediates valproic acid-induced neuronal differentiation of neural stem cells through epigenetic modifications. Stem cell reports 8:1256–1269. https://doi.org/10.1016/j.stemcr.2017.04.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  250. Zhou W, Li S (2018) Decreased levels of serum retinoic acid in chinese children with autism spectrum disorder. Psychiatry Res 269:469–473. https://doi.org/10.1016/j.psychres.2018.08.091

    CAS  Article  PubMed  Google Scholar 

  251. Zhou L, An N, Haydon RC et al (2003) Tyrosine kinase inhibitor STI-571/Gleevec down-regulates the beta-catenin signaling activity. Cancer Lett 193:161–170. https://doi.org/10.1016/s0304-3835(03)00013-2

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to the Department of Biochemistry of the Institute of Chemistry (IQ) of the University of São Paulo (USP, São Paulo, Brazil) for the academic support and opportunity to write this review.

Funding

R.G.C. was supported by a Visiting Professor grant (Edital 02/2019, PrInt USP/CAPES) from University of São Paulo (USP) and CAPES (Federal Agency for Superior Education and Training), Brazil.

Author information

Affiliations

Authors

Contributions

Manuscript conceptualization: RGC. Drafting the text: JB, GD, MCSB, RBA, RRA, ALPA, DP. Preparing figures: JB, GD, MCSB. Manuscript editing and formatting: JB, GD, MCS, RGC, HU. Manuscript revision: RGC, MCS, HU.

Corresponding author

Correspondence to Ricardo G. Correa.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Baranova, J., Dragunas, G., Botellho, M.C.S. et al. Autism Spectrum Disorder: Signaling Pathways and Prospective Therapeutic Targets. Cell Mol Neurobiol (2020). https://doi.org/10.1007/s10571-020-00882-7

Download citation

Keywords

  • Autism spectrum disorder
  • ASD
  • Signaling pathway
  • Neurodevelopment
  • Neuroinflammation
  • Drug target