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Deciphering the roles of glycogen synthase kinase 3 (GSK3) in the treatment of autism spectrum disorder and related syndromes

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Abstract

Autism spectrum disorder (ASD) is a complex and multifactorial neurodevelopmental disorder characterized by the presence of restricted interests and repetitive behaviors besides deficits in social communication. Syndromic ASD is a subset of ASD caused by underlying genetic disorders, most commonly Fragile X Syndrome (FXS) and Rett Syndrome (RTT). Various mutations and consequent malfunctions in core signaling pathways have been identified in ASD, including glycogen synthase kinase 3 (GSK3). A growing body of evidence suggests a key role of GSK3 dysregulation in the pathogenesis of ASD and its related disorders. Here, we provide a synopsis of the implication of GSK3 in ASD, FXS, and RTT as a promising therapeutic target for the treatment of ASD.

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References

  1. Elsabbagh M, Divan G, Koh YJ, Kim YS, Kauchali S, Marcin C, Montiel-Nava C, Patel V, Paula CS, Wang C, Yasamy MT, Fombonne E (2012) Global prevalence of autism and other pervasive developmental disorders. Autism Res 5(3):160–179. https://doi.org/10.1002/aur.239

    Article  PubMed  PubMed Central  Google Scholar 

  2. American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric Association Publishing. https://doi.org/10.1176/appi.books.9780890425596

    Article  Google Scholar 

  3. Persico AM, Napolioni V (2013) Autism genetics. Behav Brain Res 251:95–112. https://doi.org/10.1016/j.bbr.2013.06.012

    Article  PubMed  Google Scholar 

  4. Lai M-C, Lombardo MV, Baron-Cohen S (2014) Autism. Lancet 383(9920):896–910. https://doi.org/10.1016/s0140-6736(13)61539-1

    Article  PubMed  Google Scholar 

  5. Hur E-M, Zhou F-Q (2010) GSK3 signalling in neural development. Nat Rev Neurosci 11(8):539–551. https://doi.org/10.1038/nrn2870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lopez-Tobon A, Villa CE, Cheroni C, Trattaro S, Caporale N, Conforti P, Iennaco R, Lachgar M, Rigoli MT, Marco de la Cruz B, Lo Riso P, Tenderini E, Troglio F, De Simone M, Liste-Noya I, Macino G, Pagani M, Cattaneo E, Testa G (2019) Human cortical organoids expose a differential function of GSK3 on cortical neurogenesis. Stem Cell Rep 13(5):847–861. https://doi.org/10.1016/j.stemcr.2019.09.005

    Article  CAS  Google Scholar 

  7. Duka T, Duka V, Joyce JN, Sidhu A (2009) Alpha-Synuclein contributes to GSK-3beta-catalyzed Tau phosphorylation in Parkinson’s disease models. FASEB J 23(9):2820–2830. https://doi.org/10.1096/fj.08-120410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Loomes R, Hull L, Mandy WPL (2017) What is the male-to-female ratio in autism spectrum disorder? A systematic review and meta-analysis. J Am Acad Child Adolesc Psychiatry 56(6):466–474. https://doi.org/10.1016/j.jaac.2017.03.013

    Article  PubMed  Google Scholar 

  9. Mukherjee SB (2017) Autism spectrum disorders—diagnosis and management. Indian J Pediatr 84(4):307–314. https://doi.org/10.1007/s12098-016-2272-2

    Article  PubMed  Google Scholar 

  10. Hodges H, Fealko C, Soares N (2020) Autism spectrum disorder: definition, epidemiology, causes, and clinical evaluation. Transl Pediatr 9(Suppl 1):S55–S65. https://doi.org/10.21037/tp.2019.09.09

    Article  PubMed  PubMed Central  Google Scholar 

  11. Fett-Conte AC, Bossolani-Martins AL, Rosan DBA (2015) Etiology of autism the complexity of risk factors in autism spectrum disorder. In: Autism spectrum disorder—recent advances. IntechOpen. https://doi.org/10.5772/59109

  12. Yoo H (2015) Genetics of autism spectrum disorder: current status and possible clinical applications. Exp Neurobiol 24(4):257–272. https://doi.org/10.5607/en.2015.24.4.257

    Article  PubMed  PubMed Central  Google Scholar 

  13. Schaaf CP, Zoghbi HY (2011) Solving the autism puzzle a few pieces at a time. Neuron 70(5):806–808. https://doi.org/10.1016/j.neuron.2011.05.025

    Article  CAS  PubMed  Google Scholar 

  14. Varela-Nallar L, Inestrosa NC (2013) Wnt signaling in the regulation of adult hippocampal neurogenesis. Front Cell Neurosci 7:100. https://doi.org/10.3389/fncel.2013.00100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kumar S, Reynolds K, Ji Y, Gu R, Rai S, Zhou CJ (2019) Impaired neurodevelopmental pathways in autism spectrum disorder: a review of signaling mechanisms and crosstalk. J Neurodev Disord 11(1):10. https://doi.org/10.1186/s11689-019-9268-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Moon RT, Kohn AD, De Ferrari GV, Kaykas A (2004) WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 5(9):691–701. https://doi.org/10.1038/nrg1427

    Article  CAS  PubMed  Google Scholar 

  17. Caracci MO, Avila ME, De Ferrari GV (2016) Synaptic Wnt/GSK3beta signaling hub in Autism. Neural Plast 2016:9603751. https://doi.org/10.1155/2016/9603751

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dong F, Jiang J, McSweeney C, Zou D, Liu L, Mao Y (2016) Deletion of CTNNB1 in inhibitory circuitry contributes to autism-associated behavioral defects. Hum Mol Genet 25(13):2738–2751. https://doi.org/10.1093/hmg/ddw131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Platt RJ, Zhou Y, Slaymaker IM, Shetty AS, Weisbach NR, Kim JA, Sharma J, Desai M, Sood S, Kempton HR, Crabtree GR, Feng G, Zhang F (2017) Chd8 mutation leads to autistic-like behaviors and impaired striatal circuits. Cell Rep 19(2):335–350. https://doi.org/10.1016/j.celrep.2017.03.052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Sestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485(7397):237–241. https://doi.org/10.1038/nature10945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, Witherspoon K, Gerdts J, Baker C, Vulto-van Silfhout AT, Schuurs-Hoeijmakers JH, Fichera M, Bosco P, Buono S, Alberti A, Failla P, Peeters H, Steyaert J, Vissers L, Francescatto L, Mefford HC, Rosenfeld JA, Bakken T, O’Roak BJ, Pawlus M, Moon R, Shendure J, Amaral DG, Lein E, Rankin J, Romano C, de Vries BBA, Katsanis N, Eichler EE (2014) Disruptive CHD8 mutations define a subtype of autism early in development. Cell 158(2):263–276. https://doi.org/10.1016/j.cell.2014.06.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Borrie SC, Brems H, Legius E, Bagni C (2017) Cognitive dysfunctions in intellectual disabilities: the contributions of the Ras-MAPK and PI3K-AKT-mTOR pathways. Annu Rev Genomics Hum Genet 18:115–142. https://doi.org/10.1146/annurev-genom-091416-035332

    Article  CAS  PubMed  Google Scholar 

  24. Li X, Wu C, Chen N, Gu H, Yen A, Cao L, Wang E, Wang L (2016) PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget 7(22):33440–33450. https://doi.org/10.18632/oncotarget.7961

    Article  PubMed  PubMed Central  Google Scholar 

  25. Zhang X, He X, Li Q, Kong X, Ou Z, Zhang L, Gong Z, Long D, Li J, Zhang M, Ji W, Zhang W, Xu L, Xuan A (2017) PI3K/AKT/mTOR signaling mediates valproic acid-induced neuronal differentiation of neural stem cells through epigenetic modifications. Stem Cell Rep 8(5):1256–1269. https://doi.org/10.1016/j.stemcr.2017.04.006

    Article  CAS  Google Scholar 

  26. Winden KD, Ebrahimi-Fakhari D, Sahin M (2018) Abnormal mTOR activation in autism. Annu Rev Neurosci 41:1–23. https://doi.org/10.1146/annurev-neuro-080317-061747

    Article  CAS  PubMed  Google Scholar 

  27. Butler MG, Dasouki MJ, Zhou XP, Talebizadeh Z, Brown M, Takahashi TN, Miles JH, Wang CH, Stratton R, Pilarski R, Eng C (2005) Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 42(4):318–321. https://doi.org/10.1136/jmg.2004.024646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Caban C, Khan N, Hasbani DM, Crino PB (2017) Genetics of tuberous sclerosis complex: implications for clinical practice. Appl Clin Genet 10:1–8. https://doi.org/10.2147/TACG.S90262

    Article  CAS  PubMed  Google Scholar 

  29. Lugo JN, Smith GD, Arbuckle EP, White J, Holley AJ, Floruta CM, Ahmed N, Gomez MC, Okonkwo O (2014) Deletion of PTEN produces autism-like behavioral deficits and alterations in synaptic proteins. Front Mol Neurosci 7:27. https://doi.org/10.3389/fnmol.2014.00027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, Li Y, Baker SJ, Parada LF (2006) Pten regulates neuronal arborization and social interaction in mice. Neuron 50(3):377–388. https://doi.org/10.1016/j.neuron.2006.03.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Schroeder JC, Reim D, Boeckers TM, Schmeisser MJ (2017) Genetic animal models for autism spectrum disorder. Curr Top Behav Neurosci 30:311–324. https://doi.org/10.1007/7854_2015_407

    Article  PubMed  Google Scholar 

  32. Qin L, Dai X, Yin Y (2016) Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats. Mol Cell Neurosci 75:27–35. https://doi.org/10.1016/j.mcn.2016.06.004

    Article  CAS  PubMed  Google Scholar 

  33. Kotajima-Murakami H, Kobayashi T, Kashii H, Sato A, Hagino Y, Tanaka M, Nishito Y, Takamatsu Y, Uchino S, Ikeda K (2019) Effects of rapamycin on social interaction deficits and gene expression in mice exposed to valproic acid in utero. Mol Brain 12(1):3. https://doi.org/10.1186/s13041-018-0423-2

    Article  PubMed  PubMed Central  Google Scholar 

  34. 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(12):882–885

    Google Scholar 

  35. Lai X, Wu X, Hou N, Liu S, Li Q, Yang T, Miao J, Dong Z, Chen J, Li T (2018) Vitamin A deficiency induces autistic-like behaviors in rats by regulating the RARβ-CD38-oxytocin axis in the hypothalamus. Mol Nutr Food Res. https://doi.org/10.1002/mnfr.201700754

    Article  PubMed  Google Scholar 

  36. 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(4):e0153329. https://doi.org/10.1371/journal.pone.0153329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pandey MK, DeGrado TR (2016) Glycogen synthase kinase-3 (GSK-3)-targeted therapy and imaging. Theranostics 6(4):571–593. https://doi.org/10.7150/thno.14334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cohen P (1979) The hormonal control of glycogen metabolism in mammalian muscle by multivalent phosphorylation. Biochem Soc Trans 7(3):459–480. https://doi.org/10.1042/bst0070459

    Article  CAS  PubMed  Google Scholar 

  39. Embi N, Rylatt DB, Cohen P (1980) Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem 107(2):519–527

    Article  CAS  Google Scholar 

  40. Summers SA, Kao AW, Kohn AD, Backus GS, Roth RA, Pessin JE, Birnbaum MJ (1999) The role of glycogen synthase kinase 3beta in insulin-stimulated glucose metabolism. J Biol Chem 274(25):17934–17940. https://doi.org/10.1074/jbc.274.25.17934

    Article  CAS  PubMed  Google Scholar 

  41. Montori-Grau M, Tarrats N, Osorio-Conles O, Orozco A, Serrano-Marco L, Vazquez-Carrera M, Gomez-Foix AM (2013) Glucose dependence of glycogen synthase activity regulation by GSK3 and MEK/ERK inhibitors and angiotensin-(1–7) action on these pathways in cultured human myotubes. Cell Signal 25(5):1318–1327. https://doi.org/10.1016/j.cellsig.2013.02.014

    Article  CAS  PubMed  Google Scholar 

  42. Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65(4):391–426. https://doi.org/10.1016/s0301-0082(01)00011-9

    Article  CAS  PubMed  Google Scholar 

  43. Tullai JW, Chen J, Schaffer ME, Kamenetsky E, Kasif S, Cooper GM (2007) Glycogen synthase kinase-3 represses cyclic AMP response element-binding protein (CREB)-targeted immediate early genes in quiescent cells. J Biol Chem 282(13):9482–9491. https://doi.org/10.1074/jbc.M700067200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Morfini G, Szebenyi G, Elluru R, Ratner N, Brady ST (2002) Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J 21(3):281–293. https://doi.org/10.1093/emboj/21.3.281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cui H, Meng Y, Bulleit RF (1998) Inhibition of glycogen synthase kinase 3beta activity regulates proliferation of cultured cerebellar granule cells. Brain Res Dev Brain Res 111(2):177–188. https://doi.org/10.1016/s0165-3806(98)00136-9

    Article  CAS  PubMed  Google Scholar 

  46. Taylor A, Rudd CE (2020) Glycogen synthase kinase 3 (GSK-3) controls T-cell motility and interactions with antigen presenting cells. BMC Res Notes 13(1):163. https://doi.org/10.1186/s13104-020-04971-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jacobs KM, Bhave SR, Ferraro DJ, Jaboin JJ, Hallahan DE, Thotala D (2012) GSK-3beta: a bifunctional role in cell death pathways. Int J Cell Biol 2012:930710. https://doi.org/10.1155/2012/930710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Watcharasit P, Bijur GN, Zmijewski JW, Song L, Zmijewska A, Chen X, Johnson GVW, Jope RS (2002) Direct, activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage. Proc Natl Acad Sci USA 99(12):7951–7955. https://doi.org/10.1073/pnas.122062299

    Article  CAS  PubMed  Google Scholar 

  49. Cole A (2012) GSK3 as a Sensor Determining Cell Fate in the Brain. Front Mol Neurosci 5:4

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ferrer I, Barrachina M, Puig B (2002) Glycogen synthase kinase-3 is associated with neuronal and glial hyperphosphorylated tau deposits in Alzheimer’s disease, Pick’s disease, progressive supranuclear palsy and corticobasal degeneration. Acta Neuropathol 104(6):583–591. https://doi.org/10.1007/s00401-002-0587-8

    Article  CAS  PubMed  Google Scholar 

  51. Woodgett JR (1990) Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J 9(8):2431–2438

    Article  CAS  Google Scholar 

  52. Cortes-Vieyra R, Silva-Garcia O, Oviedo-Boyso J, Huante-Mendoza A, Bravo-Patino A, Valdez-Alarcon JJ, Finlay BB, Baizabal-Aguirre VM (2015) The glycogen synthase kinase 3alpha and beta Isoforms differentially regulates interleukin-12p40 expression in endothelial cells stimulated with peptidoglycan from Staphylococcus aureus. PLoS ONE 10(7):e0132867. https://doi.org/10.1371/journal.pone.0132867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Liang MH, Chuang DM (2006) Differential roles of glycogen synthase kinase-3 isoforms in the regulation of transcriptional activation. J Biol Chem 281(41):30479–30484. https://doi.org/10.1074/jbc.M607468200

    Article  CAS  PubMed  Google Scholar 

  54. Kaidanovich-Beilin O, Woodgett JR (2011) GSK-3: functional insights from cell biology and animal models. Front Mol Neurosci 4:40. https://doi.org/10.3389/fnmol.2011.00040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kaidanovich-Beilin O, Beaulieu J-M, Jope RS, Woodgett JR (2012) Neurological functions of the masterswitch protein kinase - gsk-3. Front Mol Neurosci 5:48–48. https://doi.org/10.3389/fnmol.2012.00048

    Article  PubMed  PubMed Central  Google Scholar 

  56. Pandey GN, Dwivedi Y, Rizavi HS, Teppen T, Gaszner GL, Roberts RC, Conley RR (2009) GSK-3beta gene expression in human postmortem brain: regional distribution, effects of age and suicide. Neurochem Res 34(2):274–285. https://doi.org/10.1007/s11064-008-9770-1

    Article  CAS  PubMed  Google Scholar 

  57. Forde JE, Dale TC (2007) Glycogen synthase kinase 3: a key regulator of cellular fate. Cell Mol Life Sci 64(15):1930–1944. https://doi.org/10.1007/s00018-007-7045-7

    Article  CAS  PubMed  Google Scholar 

  58. Mukai F, Ishiguro K, Sano Y, Fujita SC (2002) Alternative splicing isoform of tau protein kinase I/glycogen synthase kinase 3beta. J Neurochem 81(5):1073–1083. https://doi.org/10.1046/j.1471-4159.2002.00918.x

    Article  CAS  PubMed  Google Scholar 

  59. Soutar MP, Kim WY, Williamson R, Peggie M, Hastie CJ, McLauchlan H, Snider WD, Gordon-Weeks PR, Sutherland C (2010) Evidence that glycogen synthase kinase-3 isoforms have distinct substrate preference in the brain. J Neurochem 115(4):974–983. https://doi.org/10.1111/j.1471-4159.2010.06988.x

    Article  CAS  PubMed  Google Scholar 

  60. Saeki K, Machida M, Kinoshita Y, Takasawa R, Tanuma S (2011) Glycogen synthase kinase-3β2 has lower phosphorylation activity to tau than glycogen synthase kinase-3β1. Biol Pharm Bull 34(1):146–149. https://doi.org/10.1248/bpb.34.146

    Article  CAS  PubMed  Google Scholar 

  61. Zhang F, Phiel CJ, Spece L, Gurvich N, Klein PS (2003) Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. Evidence for autoregulation of GSK-3. J Biol Chem 278(35):33067–33077. https://doi.org/10.1074/jbc.M212635200

    Article  CAS  PubMed  Google Scholar 

  62. Jope RS, Johnson GV (2004) The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 29(2):95–102. https://doi.org/10.1016/j.tibs.2003.12.004

    Article  CAS  PubMed  Google Scholar 

  63. Sayas CL, Ariaens A, Ponsioen B, Moolenaar WH (2006) GSK-3 is activated by the tyrosine kinase Pyk2 during LPA1-mediated neurite retraction. Mol Biol Cell 17(4):1834–1844. https://doi.org/10.1091/mbc.e05-07-0688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hughes K, Nikolakaki E, Plyte SE, Totty NF, Woodgett JR (1993) Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J 12(2):803–808

    Article  CAS  Google Scholar 

  65. Cole A, Frame S, Cohen P (2004) Further evidence that the tyrosine phosphorylation of glycogen synthase kinase-3 (GSK3) in mammalian cells is an autophosphorylation event. Biochem J 377(Pt 1):249–255. https://doi.org/10.1042/BJ20031259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bijur GN, Jope RS (2003) Glycogen synthase kinase-3 beta is highly activated in nuclei and mitochondria. NeuroReport 14(18):2415–2419. https://doi.org/10.1097/00001756-200312190-00025

    Article  CAS  PubMed  Google Scholar 

  67. Azoulay-Alfaguter I, Yaffe Y, Licht-Murava A, Urbanska M, Jaworski J, Pietrokovski S, Hirschberg K, Eldar-Finkelman H (2011) Distinct molecular regulation of glycogen synthase kinase-3alpha isozyme controlled by its N-terminal region: functional role in calcium/calpain signaling. J Biol Chem 286(15):13470–13480. https://doi.org/10.1074/jbc.M110.127969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hoshi M, Sato M, Kondo S, Takashima A, Noguchi K, Takahashi M, Ishiguro K, Imahori K (1995) Different localization of tau protein kinase I/glycogen synthase kinase-3 beta from glycogen synthase kinase-3 alpha in cerebellum mitochondria. J Biochem 118(4):683–685. https://doi.org/10.1093/oxfordjournals.jbchem.a124965

    Article  CAS  PubMed  Google Scholar 

  69. Bijur GN, Jope RS (2001) Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3 beta. J Biol Chem 276(40):37436–37442. https://doi.org/10.1074/jbc.M105725200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yang K, Chen Z, Gao J, Shi W, Li L, Jiang S, Hu H, Liu Z, Xu D, Wu L (2017) The key roles of GSK-3β in regulating mitochondrial activity. Cell Physiol Biochem 44(4):1445–1459. https://doi.org/10.1159/000485580

    Article  CAS  PubMed  Google Scholar 

  71. Garrido JJ, Simon D, Varea O, Wandosell F (2007) GSK3 alpha and GSK3 beta are necessary for axon formation. FEBS Lett 581(8):1579–1586. https://doi.org/10.1016/j.febslet.2007.03.018

    Article  CAS  PubMed  Google Scholar 

  72. Medina M, Wandosell F (2011) Deconstructing GSK-3: The Fine Regulation of Its Activity. Int J Alzheimer’s Dis 2011:479249. https://doi.org/10.4061/2011/479249

    Article  CAS  Google Scholar 

  73. Dajani R, Fraser E, Roe SM, Young N, Good V, Dale TC, Pearl LH (2001) Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell 105(6):721–732. https://doi.org/10.1016/s0092-8674(01)00374-9

    Article  CAS  PubMed  Google Scholar 

  74. Frame S, Cohen P, Biondi RM (2001) A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol Cell 7(6):1321–1327. https://doi.org/10.1016/s1097-2765(01)00253-2

    Article  CAS  PubMed  Google Scholar 

  75. Fiol CJ, Mahrenholz AM, Wang Y, Roeske RW, Roach PJ (1987) Formation of protein kinase recognition sites by covalent modification of the substrate. Molecular mechanism for the synergistic action of casein kinase II and glycogen synthase kinase 3. J Biol Chem 262 (29):14042–14048

  76. Wang Y, Roach PJ (1993) Inactivation of rabbit muscle glycogen synthase by glycogen synthase kinase-3. Dominant role of the phosphorylation of Ser-640 (site-3a). J Biol Chem 268 (32):23876–23880

  77. Sengupta A, Wu Q, Grundke-Iqbal I, Iqbal K, Singh TJ (1997) Potentiation of GSK-3-catalyzed Alzheimer-like phosphorylation of human tau by cdk5. Mol Cell Biochem 167(1–2):99–105. https://doi.org/10.1023/a:1006883924775

    Article  CAS  PubMed  Google Scholar 

  78. Nishimura I, Yang Y, Lu B (2004) PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila. Cell 116(5):671–682. https://doi.org/10.1016/s0092-8674(04)00170-9

    Article  CAS  PubMed  Google Scholar 

  79. Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, Ben-Neriah Y, Alkalay I (2002) Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev 16(9):1066–1076. https://doi.org/10.1101/gad.230302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Jia J, Amanai K, Wang G, Tang J, Wang B, Jiang J (2002) Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus. Nature 416(6880):548–552. https://doi.org/10.1038/nature733

    Article  CAS  PubMed  Google Scholar 

  81. Twomey C, McCarthy JV (2006) Presenilin-1 is an unprimed glycogen synthase kinase-3beta substrate. FEBS Lett 580(17):4015–4020. https://doi.org/10.1016/j.febslet.2006.06.035

    Article  CAS  PubMed  Google Scholar 

  82. Goni-Oliver P, Lucas JJ, Avila J, Hernandez F (2007) N-terminal cleavage of GSK-3 by calpain: a new form of GSK-3 regulation. J Biol Chem 282(31):22406–22413. https://doi.org/10.1074/jbc.M702793200

    Article  CAS  PubMed  Google Scholar 

  83. Kandasamy AD, Schulz R (2009) Glycogen synthase kinase-3beta is activated by matrix metalloproteinase-2 mediated proteolysis in cardiomyoblasts. Cardiovasc Res 83(4):698–706. https://doi.org/10.1093/cvr/cvp175

    Article  CAS  PubMed  Google Scholar 

  84. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378(6559):785–789. https://doi.org/10.1038/378785a0

    Article  CAS  PubMed  Google Scholar 

  85. Ding VW, Chen RH, McCormick F (2000) Differential regulation of glycogen synthase kinase 3beta by insulin and Wnt signaling. J Biol Chem 275(42):32475–32481. https://doi.org/10.1074/jbc.M005342200

    Article  CAS  PubMed  Google Scholar 

  86. Al-Khouri AM, Ma Y, Togo SH, Williams S, Mustelin T (2005) Cooperative phosphorylation of the tumor suppressor phosphatase and tensin homologue (PTEN) by casein kinases and glycogen synthase kinase 3beta. J Biol Chem 280(42):35195–35202. https://doi.org/10.1074/jbc.M503045200

    Article  CAS  PubMed  Google Scholar 

  87. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL (2006) TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126(5):955–968. https://doi.org/10.1016/j.cell.2006.06.055

    Article  CAS  PubMed  Google Scholar 

  88. Mak BC, Kenerson HL, Aicher LD, Barnes EA, Yeung RS (2005) Aberrant beta-catenin signaling in tuberous sclerosis. Am J Pathol 167(1):107–116. https://doi.org/10.1016/s0002-9440(10)62958-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Koo J, Wu X, Mao Z, Khuri FR, Sun SY (2015) Rictor undergoes glycogen synthase kinase 3 (GSK3)-dependent, FBXW7-mediated ubiquitination and proteasomal degradation. J Biol Chem 290(22):14120–14129. https://doi.org/10.1074/jbc.M114.633057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Gulen MF, Bulek K, Xiao H, Yu M, Gao J, Sun L, Beurel E, Kaidanovich-Beilin O, Fox PL, DiCorleto PE, Wang JA, Qin J, Wald DN, Woodgett JR, Jope RS, Carman J, Dongre A, Li X (2012) Inactivation of the enzyme GSK3α by the kinase IKKi promotes AKT-mTOR signaling pathway that mediates interleukin-1-induced Th17 cell maintenance. Immunity 37(5):800–812. https://doi.org/10.1016/j.immuni.2012.08.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lathia JD, Mattson MP, Cheng A (2008) Notch: from neural development to neurological disorders. J Neurochem 107(6):1471–1481. https://doi.org/10.1111/j.1471-4159.2008.05715.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Foltz DR, Santiago MC, Berechid BE, Nye JS (2002) Glycogen synthase kinase-3beta modulates notch signaling and stability. Curr Biol 12(12):1006–1011. https://doi.org/10.1016/s0960-9822(02)00888-6

    Article  CAS  PubMed  Google Scholar 

  93. Espinosa L, Ingles-Esteve J, Aguilera C, Bigas A (2003) Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways. J Biol Chem 278(34):32227–32235. https://doi.org/10.1074/jbc.M304001200

    Article  CAS  PubMed  Google Scholar 

  94. Choudhry Z, Rikani AA, Choudhry AM, Tariq S, Zakaria F, Asghar MW, Sarfraz MK, Haider K, Shafiq AA, Mobassarah NJ (2014) Sonic hedgehog signalling pathway: a complex network. Ann Neurosci 21(1):28–31. https://doi.org/10.5214/ans.0972.7531.210109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Jiang J, Hui CC (2008) Hedgehog signaling in development and cancer. Dev Cell 15(6):801–812. https://doi.org/10.1016/j.devcel.2008.11.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Chen Y, Yue S, Xie L, Pu XH, Jin T, Cheng SY (2011) Dual Phosphorylation of suppressor of fused (Sufu) by PKA and GSK3beta regulates its stability and localization in the primary cilium. J Biol Chem 286(15):13502–13511. https://doi.org/10.1074/jbc.M110.217604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Chen G, Bower KA, Xu M, Ding M, Shi X, Ke ZJ, Luo J (2009) Cyanidin-3-glucoside reverses ethanol-induced inhibition of neurite outgrowth: role of glycogen synthase kinase 3 Beta. Neurotoxicol Res 15(4):321–331. https://doi.org/10.1007/s12640-009-9036-y

    Article  CAS  Google Scholar 

  98. Gao L, Zhao M, Ye W, Huang J, Chu J, Yan S, Wang C, Zeng R (2016) Inhibition of glycogen synthase kinase-3 (GSK3) promotes the neural differentiation of full-term amniotic fluid-derived stem cells towards neural progenitor cells. Tissue Cell 48(4):312–320. https://doi.org/10.1016/j.tice.2016.06.001

    Article  CAS  PubMed  Google Scholar 

  99. Barnes AP, Lilley BN, Pan YA, Plummer LJ, Powell AW, Raines AN, Sanes JR, Polleux F (2007) LKB1 and SAD kinases define a pathway required for the polarization of cortical neurons. Cell 129(3):549–563. https://doi.org/10.1016/j.cell.2007.03.025

    Article  CAS  PubMed  Google Scholar 

  100. Gärtner A, Huang X, Hall A (2006) Neuronal polarity is regulated by glycogen synthase kinase-3 (GSK-3β) independently of Akt/PKB serine phosphorylation. J Cell Sci 119(19):3927. https://doi.org/10.1242/jcs.03159

    Article  CAS  PubMed  Google Scholar 

  101. Jiang H, Guo W, Liang X, Rao Y (2005) Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3beta and its upstream regulators. Cell 120(1):123–135. https://doi.org/10.1016/j.cell.2004.12.033

    Article  CAS  PubMed  Google Scholar 

  102. Rahimi-Balaei M, Bergen H, Kong J, Marzban H (2018) Neuronal migration during development of the cerebellum. Front Cell Neurosci 12:484. https://doi.org/10.3389/fncel.2018.00484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Morgan-Smith M, Wu Y, Zhu X, Pringle J, Snider WD (2014) GSK-3 signaling in developing cortical neurons is essential for radial migration and dendritic orientation. Elife 3:e02663. https://doi.org/10.7554/eLife.02663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Asada N, Sanada K (2010) LKB1-mediated spatial control of GSK3beta and adenomatous polyposis coli contributes to centrosomal forward movement and neuronal migration in the developing neocortex. J Neurosci 30(26):8852–8865. https://doi.org/10.1523/JNEUROSCI.6140-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yang X, Klein R, Tian X, Cheng HT, Kopan R, Shen J (2004) Notch activation induces apoptosis in neural progenitor cells through a p53-dependent pathway. Dev Biol 269(1):81–94. https://doi.org/10.1016/j.ydbio.2004.01.014

    Article  CAS  PubMed  Google Scholar 

  106. Depaepe V, Suarez-Gonzalez N, Dufour A, Passante L, Gorski JA, Jones KR, Ledent C, Vanderhaeghen P (2005) Ephrin signalling controls brain size by regulating apoptosis of neural progenitors. Nature 435(7046):1244–1250. https://doi.org/10.1038/nature03651

    Article  CAS  PubMed  Google Scholar 

  107. Eom T-Y, Roth KA, Jope RS (2007) Neural precursor cells are protected from apoptosis induced by trophic factor withdrawal or genotoxic stress by inhibitors of glycogen synthase kinase 3. J Biol Chem 282(31):22856–22864. https://doi.org/10.1074/jbc.M702973200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J (2001) Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 20(1–2):27–39. https://doi.org/10.1093/emboj/20.1.27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Hetman M, Cavanaugh JE, Kimelman D, Xia Z (2000) Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal. J Neurosci 20(7):2567–2574. https://doi.org/10.1523/JNEUROSCI.20-07-02567.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kozikowski AP, Gaisina IN, Petukhov PA, Sridhar J, King LT, Blond SY, Duka T, Rusnak M, Sidhu A (2006) Highly potent and specific GSK-3beta inhibitors that block tau phosphorylation and decrease alpha-synuclein protein expression in a cellular model of Parkinson’s disease. ChemMedChem 1(2):256–266. https://doi.org/10.1002/cmdc.200500039

    Article  CAS  PubMed  Google Scholar 

  111. Beaulieu JM, Sotnikova TD, Yao WD, Kockeritz L, Woodgett JR, Gainetdinov RR, Caron MG (2004) Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci USA 101(14):5099–5104. https://doi.org/10.1073/pnas.0307921101

    Article  CAS  PubMed  Google Scholar 

  112. Li X, Liu M, Cai Z, Wang G, Li X (2010) Regulation of glycogen synthase kinase-3 during bipolar mania treatment. Bipolar Disord 12(7):741–752. https://doi.org/10.1111/j.1399-5618.2010.00866.x

    Article  PubMed  PubMed Central  Google Scholar 

  113. Onore C, Yang H, Van de Water J, Ashwood P (2017) Dynamic Akt/mTOR signaling in children with autism spectrum disorder. Front Pediatr 5:43

  114. Wu HF, Chen PS, Chen YJ, Lee CW, Chen IT, Lin HC (2017) Alleviation of N-methyl-D-aspartate receptor-dependent long-term depression via regulation of the glycogen synthase kinase-3beta pathway in the amygdala of a valproic acid-induced animal model of autism. Mol Neurobiol 54(7):5264–5276. https://doi.org/10.1007/s12035-016-0074-1

    Article  CAS  PubMed  Google Scholar 

  115. Schneider T, Przewlocki R (2005) Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 30(1):80–89. https://doi.org/10.1038/sj.npp.1300518

    Article  CAS  PubMed  Google Scholar 

  116. Go HS, Kim KC, Choi CS, Jeon SJ, Kwon KJ, Han SH, Lee J, Cheong JH, Ryu JH, Kim CH, Ko KH, Shin CY (2012) Prenatal exposure to valproic acid increases the neural progenitor cell pool and induces macrocephaly in rat brain via a mechanism involving the GSK-3beta/beta-catenin pathway. Neuropharmacology 63(6):1028–1041. https://doi.org/10.1016/j.neuropharm.2012.07.028

    Article  CAS  PubMed  Google Scholar 

  117. Courchesne E, Carper R, Akshoomoff N (2003) Evidence of brain overgrowth in the first year of life in autism. JAMA 290(3):337–344. https://doi.org/10.1001/jama.290.3.337

    Article  PubMed  Google Scholar 

  118. Courchesne E, Mouton PR, Calhoun ME, Semendeferi K, Ahrens-Barbeau C, Hallet MJ, Barnes CC, Pierce K (2011) Neuron number and size in prefrontal cortex of children with autism. JAMA 306(18):2001–2010. https://doi.org/10.1001/jama.2011.1638

    Article  CAS  PubMed  Google Scholar 

  119. Chanda S, Ang CE, Lee QY, Ghebrial M, Haag D, Shibuya Y, Wernig M, Sudhof TC (2019) Direct reprogramming of human neurons identifies MARCKSL1 as a pathogenic mediator of valproic acid-induced teratogenicity. Cell Stem Cell 25(1):103–119. https://doi.org/10.1016/j.stem.2019.04.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhang Y, Sun Y, Wang F, Wang Z, Peng Y, Li R (2012) Downregulating the canonical Wnt/beta-catenin signaling pathway attenuates the susceptibility to autism-like phenotypes by decreasing oxidative stress. Neurochem Res 37(7):1409–1419. https://doi.org/10.1007/s11064-012-0724-2

    Article  CAS  PubMed  Google Scholar 

  121. Zhang Y, Yang C, Yuan G, Wang Z, Cui W, Li R (2015) Sulindac attenuates valproic acid-induced oxidative stress levels in primary cultured cortical neurons and ameliorates repetitive/stereotypic-like movement disorders in Wistar rats prenatally exposed to valproic acid. Int J Mol Med 35(1):263–270. https://doi.org/10.3892/ijmm.2014.1996

    Article  CAS  PubMed  Google Scholar 

  122. Gilman SR, Iossifov I, Levy D, Ronemus M, Wigler M, Vitkup D (2011) Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 70(5):898–907. https://doi.org/10.1016/j.neuron.2011.05.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Hutsler JJ, Zhang H (2010) Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res 1309:83–94. https://doi.org/10.1016/j.brainres.2009.09.120

    Article  CAS  PubMed  Google Scholar 

  124. Tang G, Gudsnuk K, Kuo SH, Cotrina ML, Rosoklija G, Sosunov A, Sonders MS, Kanter E, Castagna C, Yamamoto A, Yue Z, Arancio O, Peterson BS, Champagne F, Dwork AJ, Goldman J, Sulzer D (2014) Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83(5):1131–1143. https://doi.org/10.1016/j.neuron.2014.07.040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Boissart C, Poulet A, Georges P, Darville H, Julita E, Delorme R, Bourgeron T, Peschanski M, Benchoua A (2013) Differentiation from human pluripotent stem cells of cortical neurons of the superficial layers amenable to psychiatric disease modeling and high-throughput drug screening. Transl Psychiatry 3:e294. https://doi.org/10.1038/tp.2013.71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Ochs SM, Dorostkar MM, Aramuni G, Schon C, Filser S, Poschl J, Kremer A, Van Leuven F, Ovsepian SV, Herms J (2015) Loss of neuronal GSK3beta reduces dendritic spine stability and attenuates excitatory synaptic transmission via beta-catenin. Mol Psychiatry 20(4):482–489. https://doi.org/10.1038/mp.2014.55

    Article  CAS  PubMed  Google Scholar 

  127. Boccitto M, Doshi S, Newton IP, Nathke I, Neve R, Dong F, Mao Y, Zhai J, Zhang L, Kalb R (2016) Opposing actions of the synapse-associated protein of 97-kDa molecular weight (SAP97) and Disrupted in Schizophrenia 1 (DISC1) on Wnt/beta-catenin signaling. Neuroscience 326:22–30. https://doi.org/10.1016/j.neuroscience.2016.03.048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Martin PM, Stanley RE, Ross AP, Freitas AE, Moyer CE, Brumback AC, Iafrati J, Stapornwongkul KS, Dominguez S, Kivimae S, Mulligan KA, Pirooznia M, McCombie WR, Potash JB, Zandi PP, Purcell SM, Sanders SJ, Zuo Y, Sohal VS, Cheyette BNR (2018) DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/beta-catenin signaling. Mol Psychiatry 23(2):467–475. https://doi.org/10.1038/mp.2016.184

    Article  CAS  PubMed  Google Scholar 

  129. Arons MH, Thynne CJ, Grabrucker AM, Li D, Schoen M, Cheyne JE, Boeckers TM, Montgomery JM, Garner CC (2012) Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling. J Neurosci 32(43):14966–14978. https://doi.org/10.1523/JNEUROSCI.2215-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsater H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni MC, de Mas P, Bieth E, Roge B, Heron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T (2007) Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 39(1):25–27. https://doi.org/10.1038/ng1933

    Article  CAS  PubMed  Google Scholar 

  131. Wang M, Liu X, Hou Y, Zhang H, Kang J, Wang F, Zhao Y, Chen J, Liu X, Wang Y, Wu S (2019) Decrease of GSK-3beta activity in the anterior cingulate cortex of Shank3b (-/-) mice contributes to synaptic and social deficiency. Front Cell Neurosci 13:447. https://doi.org/10.3389/fncel.2019.00447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Fatemi SH, Stary JM, Halt AR, Realmuto GR (2001) Dysregulation of Reelin and Bcl-2 proteins in autistic cerebellum. J Autism Dev Disord 31(6):529–535. https://doi.org/10.1023/a:1013234708757

    Article  CAS  PubMed  Google Scholar 

  133. Fatemi SH, Snow AV, Stary JM, Araghi-Niknam M, Reutiman TJ, Lee S, Brooks AI, Pearce DA (2005) Reelin signaling is impaired in autism. Biol Psychiatry 57(7):777–787. https://doi.org/10.1016/j.biopsych.2004.12.018

    Article  CAS  PubMed  Google Scholar 

  134. Fatemi SH, Reutiman TJ, Folsom TD (2009) Chronic psychotropic drug treatment causes differential expression of Reelin signaling system in frontal cortex of rats. Schizophr Res 111(1–3):138–152. https://doi.org/10.1016/j.schres.2009.03.002

    Article  PubMed  Google Scholar 

  135. Chugani DC (2004) Serotonin in autism and pediatric epilepsies. Ment Retard Dev Disabil Res Rev 10(2):112–116. https://doi.org/10.1002/mrdd.20021

    Article  PubMed  Google Scholar 

  136. Thompson SL, Dulawa SC (2019) Dissecting the roles of beta-arrestin2 and GSK-3 signaling in 5-HT1BR-mediated perseverative behavior and prepulse inhibition deficits in mice. PLoS ONE 14(2):e0211239. https://doi.org/10.1371/journal.pone.0211239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Beaulieu JM, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, Wetsel WC, Gainetdinov RR, Caron MG (2008) Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci USA 105(4):1333–1338. https://doi.org/10.1073/pnas.0711496105

    Article  PubMed  Google Scholar 

  138. Wu X, Bai Y, Tan T, Li H, Xia S, Chang X, Zhou Z, Zhou W, Li T, Wang YT, Dong Z (2014) Lithium ameliorates autistic-like behaviors induced by neonatal isolation in rats. Front Behav Neurosci 8:Article e234. https://doi.org/10.3389/fnbeh.2014.00234

  139. Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey DB Jr, Moine H, Kooy RF, Tassone F, Gantois I, Sonenberg N, Mandel JL, Hagerman PJ (2017) Fragile X syndrome. Nat Rev Dis Primers 3:17065. https://doi.org/10.1038/nrdp.2017.65

    Article  PubMed  Google Scholar 

  140. Lozano R, Rosero CA, Hagerman RJ (2014) Fragile X spectrum disorders. Intractable Rare Dis Res 3(4):134–146. https://doi.org/10.5582/irdr.2014.01022

    Article  PubMed  PubMed Central  Google Scholar 

  141. Bhakar AL, Dolen G, Bear MF (2012) The pathophysiology of fragile X (and what it teaches us about synapses). Annu Rev Neurosci 35:417–443. https://doi.org/10.1146/annurev-neuro-060909-153138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Franklin AV, King MK, Palomo V, Martinez A, McMahon LL, Jope RS (2014) Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in fragile X mice. Biol Psychiatry 75(3):198–206. https://doi.org/10.1016/j.biopsych.2013.08.003

    Article  CAS  PubMed  Google Scholar 

  143. Guo W, Murthy AC, Zhang L, Johnson EB, Schaller EG, Allan AM, Zhao X (2012) Inhibition of GSK3β improves hippocampus-dependent learning and rescues neurogenesis in a mouse model of fragile X syndrome. Hum Mol Genet 21(3):681–691. https://doi.org/10.1093/hmg/ddr501

    Article  CAS  PubMed  Google Scholar 

  144. Min WW, Yuskaitis CJ, Yan Q, Sikorski C, Chen S, Jope RS, Bauchwitz RP (2009) Elevated glycogen synthase kinase-3 activity in Fragile X mice: key metabolic regulator with evidence for treatment potential. Neuropharmacology 56(2):463–472. https://doi.org/10.1016/j.neuropharm.2008.09.017

    Article  CAS  PubMed  Google Scholar 

  145. Pardo M, Beurel E, Jope RS (2017) Cotinine administration improves impaired cognition in the mouse model of Fragile X syndrome. Eur J Neurosci 45(4):490–498. https://doi.org/10.1111/ejn.13446

    Article  PubMed  Google Scholar 

  146. Yuskaitis CJ, Mines MA, King MK, Sweatt JD, Miller CA, Jope RS (2010) Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome. Biochem Pharmacol 79(4):632–646. https://doi.org/10.1016/j.bcp.2009.09.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Mines MA, Yuskaitis CJ, King MK, Beurel E, Jope RS (2010) GSK3 influences social preference and anxiety-related behaviors during social interaction in a mouse model of fragile X syndrome and autism. PLoS ONE 5(3):e9706. https://doi.org/10.1371/journal.pone.0009706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Yuskaitis CJ, Beurel E (1802) Jope RS (2010) Evidence of reactive astrocytes but not peripheral immune system activation in a mouse model of Fragile X syndrome. Biochim Biophys Acta 11:1006–1012. https://doi.org/10.1016/j.bbadis.2010.06.015

    Article  CAS  Google Scholar 

  149. Pardo M, Cheng Y, Velmeshev D, Magistri M, Eldar-Finkelman H, Martinez A, Faghihi MA, Jope RS, Beurel E (2017) Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice. JCI Insight 2(6):e91782. https://doi.org/10.1172/jci.insight.91782

    Article  PubMed  PubMed Central  Google Scholar 

  150. Luo Y, Shan G, Guo W, Smrt RD, Johnson EB, Li X, Pfeiffer RL, Szulwach KE, Duan R, Barkho BZ, Li W, Liu C, Jin P, Zhao X (2010) Fragile x mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells. PLoS Genet 6(4):e1000898. https://doi.org/10.1371/journal.pgen.1000898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Chen T, Lu JS, Song Q, Liu MG, Koga K, Descalzi G, Li YQ, Zhuo M (2014) Pharmacological rescue of cortical synaptic and network potentiation in a mouse model for fragile X syndrome. Neuropsychopharmacology 39(8):1955–1967. https://doi.org/10.1038/npp.2014.44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Vainio PJ, Tuominen RK (2001) Cotinine binding to nicotinic acetylcholine receptors in bovine chromaffin cell and rat brain membranes. Nicotine Tob Res 3(2):177–182. https://doi.org/10.1080/14622200110043095

    Article  CAS  PubMed  Google Scholar 

  153. McCamphill PK, Stoppel LJ, Senter RK, Lewis MC, Heynen AJ, Stoppel DC, Sridhar V, Collins KA, Shi X, Pan JQ, Madison J, Cottrell JR, Huber KM, Scolnick EM, Holson EB, Wagner FF, Bear MF (2020) Selective inhibition of glycogen synthase kinase 3α corrects pathophysiology in a mouse model of fragile X syndrome. Science Translat Med. https://doi.org/10.1126/scitranslmed.aam8572

    Article  Google Scholar 

  154. Trappe R, Laccone F, Cobilanschi J, Meins M, Huppke P, Hanefeld F, Engel W (2001) MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. Am J Hum Genet 68(5):1093–1101. https://doi.org/10.1086/320109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Psoni S, Sofocleous C, Traeger-Synodinos J, Kitsiou-Tzeli S, Kanavakis E, Fryssira-Kanioura H (2010) Phenotypic and genotypic variability in four males with MECP2 gene sequence aberrations including a novel deletion. Pediatr Res 67(5):551–556. https://doi.org/10.1203/PDR.0b013e3181d4ecf7

    Article  CAS  PubMed  Google Scholar 

  156. Hagberg B, Aicardi J, Dias K, Ramos O (1983) A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: report of 35 cases. Ann Neurol 14(4):471–479. https://doi.org/10.1002/ana.410140412

    Article  CAS  PubMed  Google Scholar 

  157. Schanen NC, Dahle EJ, Capozzoli F, Holm VA, Zoghbi HY, Francke U (1997) A new Rett syndrome family consistent with X-linked inheritance expands the X chromosome exclusion map. Am J Hum Genet 61(3):634–641. https://doi.org/10.1086/515525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23(2):185–188. https://doi.org/10.1038/13810

    Article  CAS  PubMed  Google Scholar 

  159. Jorge-Torres OC, Szczesna K, Roa L, Casal C, Gonzalez-Somermeyer L, Soler M, Velasco CD, Martinez-San Segundo P, Petazzi P, Saez MA, Delgado-Morales R, Fourcade S, Pujol A, Huertas D, Llobet A, Guil S, Esteller M (2018) Inhibition of Gsk3b reduces Nfkb1 signaling and rescues synaptic activity to improve the Rett syndrome phenotype in Mecp2-Knockout Mice. Cell Rep 23(6):1665–1677. https://doi.org/10.1016/j.celrep.2018.04.010

    Article  CAS  PubMed  Google Scholar 

  160. Tang X, Drotar J, Li K, Clairmont CD, Brumm AS, Sullins AJ, Wu H, Liu XS, Wang J, Gray NS, Sur M, Jaenisch R (2019) Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice. Sci Translat Med. https://doi.org/10.1126/scitranslmed.aau0164

    Article  Google Scholar 

  161. Hsu W-L, Ma Y-L, Liu Y-C, Tai DJC, Lee EHY (2020) Restoring Wnt6 signaling ameliorates behavioral deficits in MeCP2 T158A mouse model of Rett syndrome. Sci Rep 10(1):1074. https://doi.org/10.1038/s41598-020-57745-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Eldar-Finkelman H, Martinez A (2011) GSK-3 inhibitors: preclinical and clinical focus on CNS. Front Mol Neurosci 4:32–32. https://doi.org/10.3389/fnmol.2011.00032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Cade JF (1949) Lithium salts in the treatment of psychotic excitement. Med J Aust 2(10):349–352. https://doi.org/10.1080/j.1440-1614.1999.06241.x

    Article  CAS  PubMed  Google Scholar 

  164. Klein PS, Melton DA (1996) A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 93(16):8455–8459. https://doi.org/10.1073/pnas.93.16.8455

    Article  CAS  PubMed  Google Scholar 

  165. Ryves WJ, Dajani R, Pearl L, Harwood AJ (2002) Glycogen synthase kinase-3 inhibition by lithium and beryllium suggests the presence of two magnesium binding sites. Biochem Biophys Res Commun 290(3):967–972. https://doi.org/10.1006/bbrc.2001.6305

    Article  CAS  PubMed  Google Scholar 

  166. Chuang D-M, Wang Z, Chiu C-T (2011) GSK-3 as a target for lithium-induced neuroprotection against excitotoxicity in neuronal cultures and animal models of ischemic stroke. Front Mol Neurosci 4:15

    Article  CAS  Google Scholar 

  167. Watcharasit P, Bijur GN, Song L, Zhu J, Chen X, Jope RS (2003) Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53. J Biol Chem 278(49):48872–48879. https://doi.org/10.1074/jbc.M305870200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Kramer T, Schmidt B, Lo Monte F (2012) Small-molecule inhibitors of GSK-3: structural insights and their application to Alzheimer’s disease models. Int J Alzheimers Dis 2012:381029. https://doi.org/10.1155/2012/381029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Hernandez F, Nido JD, Avila J, Villanueva N (2009) GSK3 inhibitors and disease. Mini Rev Med Chem 9(9):1024–1029. https://doi.org/10.2174/138955709788922647

    Article  CAS  PubMed  Google Scholar 

  170. ter Haar E, Walters WP, Pazhanisamy S, Taslimi P, Pierce AC, Bemis GW, Salituro FG, Harbeson SL (2004) Kinase chemogenomics: targeting the human kinome for target validation and drug discovery. Mini Rev Med Chem 4(3):235–253. https://doi.org/10.2174/1389557043487367

    Article  PubMed  Google Scholar 

  171. Cross DA, Culbert AA, Chalmers KA, Facci L, Skaper SD, Reith AD (2001) Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death. J Neurochem 77(1):94–102. https://doi.org/10.1046/j.1471-4159.2001.t01-1-00251.x

    Article  CAS  PubMed  Google Scholar 

  172. Collino M, Thiemermann C, Mastrocola R, Gallicchio M, Benetti E, Miglio G, Castiglia S, Danni O, Murch O, Dianzani C, Aragno M, Fantozzi R (2008) Treatment with the glycogen synthase kinase-3beta inhibitor, TDZD-8, affects transient cerebral ischemia/reperfusion injury in the rat hippocampus. Shock. https://doi.org/10.1097/SHK.0b013e318164e762

    Article  PubMed  Google Scholar 

  173. Mazanetz MP, Fischer PM (2007) Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases. Nat Rev Drug Discovery 6(6):464–479. https://doi.org/10.1038/nrd2111

    Article  CAS  PubMed  Google Scholar 

  174. Hall AP, Escott KJ, Sanganee H, Hickling KC (2015) Preclinical toxicity of AZD7969: Effects of GSK3β inhibition in adult stem cells. Toxicol Pathol 43(3):384–399. https://doi.org/10.1177/0192623314544468

    Article  CAS  PubMed  Google Scholar 

  175. Kunnimalaiyaan S, Schwartz VK, Jackson IA, Clark Gamblin T, Kunnimalaiyaan M (2018) Antiproliferative and apoptotic effect of LY2090314, a GSK-3 inhibitor, in neuroblastoma in vitro. BMC Cancer 18(1):560–560. https://doi.org/10.1186/s12885-018-4474-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Khanfar MA, Hill RA, Kaddoumi A, El Sayed KA (2010) Discovery of novel GSK-3β inhibitors with potent in vitro and in vivo activities and excellent brain permeability using combined ligand- and structure-based virtual screening. J Med Chem 53(24):8534–8545. https://doi.org/10.1021/jm100941j

    Article  CAS  PubMed  Google Scholar 

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Author notes

  1. Mahdi Rizk and Zahraa Saker have contributed equally to this work as co-first authors.

  2. HishamF. Bahmad and Sanaa Nabha have contributed equally to this work as co-senior authors.

Authors and Affiliations

  1. Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon

    Mahdi Rizk, Zahraa Saker, Hayat Harati, Youssef Fares & Sanaa Nabha

  2. Department of Neurosurgery, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon

    Youssef Fares

  3. Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, 4300 Alton Rd, Miami Beach, FL, 33140, USA

    Hisham F. Bahmad

Authors
  1. Mahdi Rizk
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  2. Zahraa Saker
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  3. Hayat Harati
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  4. Youssef Fares
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  5. Hisham F. Bahmad
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  6. Sanaa Nabha
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Contributions

HFB and SN conceived the concept and idea of the present review. HFB and SN worked on the study design strategy and selected the topics to be discussed. MR, ZS, HFB and SN did literature searches and screened titles and abstracts for relevance. MR and ZS abstracted the data from the eligible full text articles, analyzed and interpreted the data, and drafted the manuscript. HH and YF revised the final draft of the manuscript. HFB and SN critically revised the manuscript with input from the entire team. All authors have read and approved the final draft.

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Correspondence to Sanaa Nabha.

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Rizk, M., Saker, Z., Harati, H. et al. Deciphering the roles of glycogen synthase kinase 3 (GSK3) in the treatment of autism spectrum disorder and related syndromes. Mol Biol Rep 48, 2669–2686 (2021). https://doi.org/10.1007/s11033-021-06237-9

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