Skip to main content

Advertisement

SpringerLink
Log in

MeCP2 Modulates Sex Differences in the Postsynaptic Development of the Valproate Animal Model of Autism

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Males are predominantly affected by autism spectrum disorders (ASD) with a prevalence ratio of 5:1. However, the underlying pathological mechanisms governing the male preponderance of ASD remain unclear. Recent studies suggested that epigenetic aberrations may cause synaptic dysfunctions, which might be related to the pathophysiology of ASD. In this study, we used rat offspring prenatally exposed to valproic acid (VPA) as an animal model of ASD. We found male-selective abnormalities in the kinetic profile of the excitatory glutamatergic synaptic protein expressions linked to N-methyl-d-aspartate receptor (NMDAR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and metabotropic glutamate receptor 5 (mGluR5) pathways in the prefrontal cortex of the VPA-exposed offspring at postnatal weeks 1, 2, and 4. Furthermore, VPA exposure showed a male-specific attenuation of the methyl-CpG-binding protein 2 (MeCP2) expressions both in the prefrontal cortex of offspring and in the gender-isolated neural progenitor cells (NPCs). In the gender-isolated NPCs culture, higher concentration of VPA induced an increased glutamatergic synaptic development along with decreased MeCP2 expression in both genders suggesting the role of MeCP2 in the modulation of synaptic development. In the small interfering RNA (siRNA) knock-down study, 50 pmol of Mecp2 siRNA inhibited the MeCP2 expression in male- but not in female-derived NPCs with concomitant induction of postsynaptic proteins such as PSD95. Taken together, we suggest that the male-inclined reduction of MeCP2 expression is involved in the abnormal development of glutamatergic synapse and male preponderance in the VPA animal models of ASD.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Zahn-Waxler C, Shirtcliff EA, Marceau K (2008) Disorders of childhood and adolescence: gender and psychopathology. Annu Rev Clin Psychol 4:275–303. doi:10.1146/annurev.clinpsy.3.022806.091358

    Article  PubMed  Google Scholar 

  2. Kim YS, Leventhal BL, Koh YJ, Fombonne E, Laska E, Lim EC, Cheon KA, Kim SJ, Kim YK, Lee H, Song DH, Grinker RR (2011) Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatr 168(9):904–912. doi:10.1176/appi.ajp.2011.10101532

    Article  PubMed  Google Scholar 

  3. Gillberg C, Cederlund M, Lamberg K, Zeijlon L (2006) Brief report: “the autism epidemic”. The registered prevalence of autism in a Swedish urban area. J Autism Dev Disord 36(3):429–435. doi:10.1007/s10803-006-0081-6

    Article  PubMed  Google Scholar 

  4. Baron-Cohen S (2002) The extreme male brain theory of autism. Trends Cogn Sci 6(6):248–254

    Article  PubMed  Google Scholar 

  5. Baron-Cohen S (2010) Empathizing, systemizing, and the extreme male brain theory of autism. Prog Brain Res 186:167–175. doi:10.1016/B978-0-444-53630-3.00011-7

    Article  PubMed  Google Scholar 

  6. Baron-Cohen S, Lombardo MV, Auyeung B, Ashwin E, Chakrabarti B, Knickmeyer R (2011) Why are autism spectrum conditions more prevalent in males? PLoS Biol 9(6):e1001081. doi:10.1371/journal.pbio.1001081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zhang FF, Cardarelli R, Carroll J, Fulda KG, Kaur M, Gonzalez K, Vishwanatha JK, Santella RM, Morabia A (2011) Significant differences in global genomic DNA methylation by gender and race/ethnicity in peripheral blood. Epigenetics Off J DNA Methylation Soc 6(5):623–629

    Article  CAS  Google Scholar 

  8. Boks MP, Derks EM, Weisenberger DJ, Strengman E, Janson E, Sommer IE, Kahn RS, Ophoff RA (2009) The relationship of DNA methylation with age, gender and genotype in twins and healthy controls. PLoS One 4(8):e6767. doi:10.1371/journal.pone.0006767

    Article  PubMed  PubMed Central  Google Scholar 

  9. Champagne FA, Weaver IC, Diorio J, Dymov S, Szyf M, Meaney MJ (2006) Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. Endocrinology 147(6):2909–2915. doi:10.1210/en.2005-1119

    Article  CAS  PubMed  Google Scholar 

  10. Nishijo M, Satarug S, Honda R, Tsuritani I, Aoshima K (2004) The gender differences in health effects of environmental cadmium exposure and potential mechanisms. Mol Cell Biochem 255(1–2):87–92

    Article  CAS  PubMed  Google Scholar 

  11. Kundakovic M, Gudsnuk K, Franks B, Madrid J, Miller RL, Perera FP, Champagne FA (2013) Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure. Proc Natl Acad Sci U S A 110(24):9956–9961. doi:10.1073/pnas.1214056110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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. doi:10.1038/13810

    Article  CAS  PubMed  Google Scholar 

  13. American Psychiatric Association A (2013) Diagnostic and statistical manual of mental disorders: (5th ed.). American Psychiatric Publishing

  14. Rett A (1966) On a unusual brain atrophy syndrome in hyperammonemia in childhood. Wien Med Wochenschr 116(37):723–726

    CAS  PubMed  Google Scholar 

  15. 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. doi:10.1002/ana.410140412

    Article  CAS  PubMed  Google Scholar 

  16. Laurvick CL, de Klerk N, Bower C, Christodoulou J, Ravine D, Ellaway C, Williamson S, Leonard H (2006) Rett syndrome in Australia: a review of the epidemiology. J Pediatr 148(3):347–352. doi:10.1016/j.jpeds.2005.10.037

    Article  PubMed  Google Scholar 

  17. Nagarajan RP, Hogart AR, Gwye Y, Martin MR, LaSalle JM (2006) Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics Off J DNA Methylation Soc 1(4):e1–e11

    Google Scholar 

  18. Zhang A, Shen CH, Ma SY, Ke Y, El Idrissi A (2009) Altered expression of autism-associated genes in the brain of Fragile X mouse model. Biochem Biophys Res Commun 379(4):920–923. doi:10.1016/j.bbrc.2008.12.172

    Article  CAS  PubMed  Google Scholar 

  19. Blue ME, Naidu S, Johnston MV (1999) Altered development of glutamate and GABA receptors in the basal ganglia of girls with Rett syndrome. Exp Neurol 156(2):345–352. doi:10.1006/exnr.1999.7030

    Article  CAS  PubMed  Google Scholar 

  20. Blue ME, Naidu S, Johnston MV (1999) Development of amino acid receptors in frontal cortex from girls with Rett syndrome. Ann Neurol 45(4):541–545

    Article  CAS  PubMed  Google Scholar 

  21. Blue ME, Kaufmann WE, Bressler J, Eyring C, O'Driscoll C, Naidu S, Johnston MV (2011) Temporal and regional alterations in NMDA receptor expression in Mecp2-null mice. Anat Rec (Hoboken) 294(10):1624–1634. doi:10.1002/ar.21380

    Article  CAS  Google Scholar 

  22. Kim KC, Lee DK, Go HS, Kim P, Choi CS, Kim JW, Jeon SJ, Song MR, Shin CY (2014) Pax6-dependent cortical glutamatergic neuronal differentiation regulates autism-like behavior in prenatally valproic acid-exposed rat offspring. Mol Neurobiol 49(1):512–528. doi:10.1007/s12035-013-8535-2

    Article  CAS  PubMed  Google Scholar 

  23. LeBlanc JJ, Fagiolini M (2011) Autism: a “critical period” disorder? Neural Plast 2011:921680. doi:10.1155/2011/921680

    Article  PubMed  PubMed Central  Google Scholar 

  24. Jian L, Nagarajan L, de Klerk N, Ravine D, Bower C, Anderson A, Williamson S, Christodoulou J, Leonard H (2006) Predictors of seizure onset in Rett syndrome. J Pediatr 149(4):542–547. doi:10.1016/j.jpeds.2006.06.015

    Article  PubMed  Google Scholar 

  25. Moser SJ, Weber P, Lutschg J (2007) Rett syndrome: clinical and electrophysiologic aspects. Pediatr Neurol 36(2):95–100. doi:10.1016/j.pediatrneurol.2006.10.003

    Article  PubMed  Google Scholar 

  26. Chao HT, Zoghbi HY, Rosenmund C (2007) MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56(1):58–65. doi:10.1016/j.neuron.2007.08.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chao HT, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J, Neul JL, Gong S, Lu HC, Heintz N, Ekker M, Rubenstein JL, Noebels JL, Rosenmund C, Zoghbi HY (2010) Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468(7321):263–269. doi:10.1038/nature09582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. D'Cruz JA, Wu C, Zahid T, El-Hayek Y, Zhang L, Eubanks JH (2010) Alterations of cortical and hippocampal EEG activity in MeCP2-deficient mice. Neurobiol Dis 38(1):8–16. doi:10.1016/j.nbd.2009.12.018

    Article  PubMed  Google Scholar 

  29. Calfa G, Hablitz JJ, Pozzo-Miller L (2011) Network hyperexcitability in hippocampal slices from Mecp2 mutant mice revealed by voltage-sensitive dye imaging. J Neurophysiol 105(4):1768–1784. doi:10.1152/jn.00800.2010

    Article  PubMed  PubMed Central  Google Scholar 

  30. Kim KC, Kim P, Go HS, Choi CS, Park JH, Kim HJ, Jeon SJ, Dela Pena IC, Han SH, Cheong JH, Ryu JH, Shin CY (2013) Male-specific alteration in excitatory postsynaptic development and social interaction in prenatal valproic acid exposure model of autism spectrum disorder. J Neurochem. doi:10.1111/jnc.12147

    Google Scholar 

  31. 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. doi:10.1001/jama.2011.1638

    Article  CAS  PubMed  Google Scholar 

  32. Zikopoulos B, Barbas H (2013) Altered neural connectivity in excitatory and inhibitory cortical circuits in autism. Front Hum Neurosci 7:609. doi:10.3389/fnhum.2013.00609

    Article  PubMed  PubMed Central  Google Scholar 

  33. Courchesne E, Pierce K (2005) Why the frontal cortex in autism might be talking only to itself: local over-connectivity but long-distance disconnection. Curr Opin Neurobiol 15(2):225–230. doi:10.1016/j.conb.2005.03.001

    Article  CAS  PubMed  Google Scholar 

  34. Rinaldi T, Perrodin C, Markram H (2008) Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic acid animal model of autism. Front Neural Circ 2:4. doi:10.3389/neuro.04.004.2008

    Google Scholar 

  35. 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. doi:10.1016/j.neuropharm.2012.07.028

    Article  CAS  PubMed  Google Scholar 

  36. Yang Y, Raine A (2009) Prefrontal structural and functional brain imaging findings in antisocial, violent, and psychopathic individuals: a meta-analysis. Psychiatry Res 174(2):81–88. doi:10.1016/j.pscychresns.2009.03.012

    Article  PubMed  PubMed Central  Google Scholar 

  37. Benoit BO, Savarese T, Joly M, Engstrom CM, Pang L, Reilly J, Recht LD, Ross AH, Quesenberry PJ (2001) Neurotrophin channeling of neural progenitor cell differentiation. J Neurobiol 46(4):265–280. doi:10.1002/1097-4695(200103)46:4<265::AID-NEU1007>3.0.CO;2-B

    Article  CAS  PubMed  Google Scholar 

  38. Conti L, Pollard SM, Gorba T, Reitano E, Toselli M, Biella G, Sun Y, Sanzone S, Ying QL, Cattaneo E, Smith A (2005) Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biol 3(9):e283. doi:10.1371/journal.pbio.0030283

    Article  PubMed  PubMed Central  Google Scholar 

  39. Go HS, Shin CY, Lee SH, Jeon SJ, Kim KC, Choi CS, Ko KH (2009) Increased proliferation and gliogenesis of cultured rat neural progenitor cells by lipopolysaccharide-stimulated astrocytes. Neuroimmunomodulation 16(6):365–376. doi:10.1159/000228911

    Article  CAS  PubMed  Google Scholar 

  40. Levine E, Cupp AS, Skinner MK (2000) Role of neurotropins in rat embryonic testis morphogenesis (cord formation). Biol Reprod 62(1):132–142

    Article  CAS  PubMed  Google Scholar 

  41. Xing GG, Wang R, Yang B, Zhang D (2006) Postnatal switching of NMDA receptor subunits from NR2B to NR2A in rat facial motor neurons. Eur J Neurosci 24(11):2987–2992. doi:10.1111/j.1460-9568.2006.05188.x

    Article  PubMed  Google Scholar 

  42. Rinaldi T, Kulangara K, Antoniello K, Markram H (2007) Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc Natl Acad Sci U S A 104(33):13501–13506. doi:10.1073/pnas.0704391104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lopez-Bendito G, Shigemoto R, Fairen A, Lujan R (2002) Differential distribution of group I metabotropic glutamate receptors during rat cortical development. Cereb Cortex 12(6):625–638

    Article  CAS  PubMed  Google Scholar 

  44. Munoz A, Liu XB, Jones EG (1999) Development of metabotropic glutamate receptors from trigeminal nuclei to barrel cortex in postnatal mouse. J Comp Neurol 409(4):549–566. doi:10.1002/(SICI)1096-9861(19990712)409:4<549::AID-CNE3>3.0.CO;2-I

    Article  CAS  PubMed  Google Scholar 

  45. Nosyreva ED, Huber KM (2005) Developmental switch in synaptic mechanisms of hippocampal metabotropic glutamate receptor-dependent long-term depression. J Neurosci 25(11):2992–3001. doi:10.1523/JNEUROSCI. 3652-04.2005

    Article  CAS  PubMed  Google Scholar 

  46. Walcott EC, Higgins EA, Desai NS (2011) Synaptic and intrinsic balancing during postnatal development in rat pups exposed to valproic acid in utero. J Neurosci 31(37):13097–13109. doi:10.1523/JNEUROSCI. 1341-11.2011

    Article  CAS  PubMed  Google Scholar 

  47. Kumamaru E, Egashira Y, Takenaka R, Takamori S (2014) Valproic acid selectively suppresses the formation of inhibitory synapses in cultured cortical neurons. Neurosci Lett 569:142–147. doi:10.1016/j.neulet.2014.03.066

    Article  CAS  PubMed  Google Scholar 

  48. Moldrich RX, Leanage G, She D, Dolan-Evans E, Nelson M, Reza N, Reutens DC (2013) Inhibition of histone deacetylase in utero causes sociability deficits in postnatal mice. Behav Brain Res 257:253–264. doi:10.1016/j.bbr.2013.09.049

    Article  CAS  PubMed  Google Scholar 

  49. Wang P, Zhang P, Huang J, Li M, Chen X (2013) Trichostatin A protects against cisplatin-induced ototoxicity by regulating expression of genes related to apoptosis and synaptic function. Neurotoxicology 37:51–62. doi:10.1016/j.neuro.2013.03.007

    Article  CAS  PubMed  Google Scholar 

  50. Kramer OH, Zhu P, Ostendorff HP, Golebiewski M, Tiefenbach J, Peters MA, Brill B, Groner B, Bach I, Heinzel T, Gottlicher M (2003) The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J 22(13):3411–3420. doi:10.1093/emboj/cdg315

    Article  PubMed  PubMed Central  Google Scholar 

  51. Chen WY, Weng JH, Huang CC, Chung BC (2007) Histone deacetylase inhibitors reduce steroidogenesis through SCF-mediated ubiquitination and degradation of steroidogenic factor 1 (NR5A1). Mol Cell Biol 27(20):7284–7290. doi:10.1128/MCB. 00476-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kong X, Lin Z, Liang D, Fath D, Sang N, Caro J (2006) Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1alpha. Mol Cell Biol 26(6):2019–2028. doi:10.1128/MCB. 26.6.2019-2028.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Liyanage VR, Zachariah RM, Rastegar M (2013) Decitabine alters the expression of Mecp2 isoforms via dynamic DNA methylation at the Mecp2 regulatory elements in neural stem cells. Mol Autism 4(1):46. doi:10.1186/2040-2392-4-46

    Article  PubMed  PubMed Central  Google Scholar 

  54. Dong E, Guidotti A, Grayson DR, Costa E (2007) Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters. Proc Natl Acad Sci U S A 104(11):4676–4681. doi:10.1073/pnas.0700529104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Milutinovic S, D'Alessio AC, Detich N, Szyf M (2007) Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes. Carcinogenesis 28(3):560–571. doi:10.1093/carcin/bgl167

    Article  CAS  PubMed  Google Scholar 

  56. Guidotti A, Auta J, Chen Y, Davis JM, Dong E, Gavin DP, Grayson DR, Matrisciano F, Pinna G, Satta R, Sharma RP, Tremolizzo L, Tueting P (2011) Epigenetic GABAergic targets in schizophrenia and bipolar disorder. Neuropharmacology 60(7–8):1007–1016. doi:10.1016/j.neuropharm.2010.10.021

    Article  CAS  PubMed  Google Scholar 

  57. Asai T, Bundo M, Sugawara H, Sunaga F, Ueda J, Tanaka G, Ishigooka J, Kasai K, Kato T, Iwamoto K (2013) Effect of mood stabilizers on DNA methylation in human neuroblastoma cells. Int J Neuropsychopharmacol 16(10):2285–2294. doi:10.1017/S1461145713000710

    Article  CAS  PubMed  Google Scholar 

  58. Selker EU (1998) Trichostatin A causes selective loss of DNA methylation in Neurospora. Proc Natl Acad Sci U S A 95(16):9430–9435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Yang F, Zhang L, Li J, Huang J, Wen R, Ma L, Zhou D, Li L (2010) Trichostatin A and 5-azacytidine both cause an increase in global histone H4 acetylation and a decrease in global DNA and H3K9 methylation during mitosis in maize. BMC Plant Biol 10:178. doi:10.1186/1471-2229-10-178

    Article  PubMed  PubMed Central  Google Scholar 

  60. Palomero-Gallagher N, Bidmon HJ, Zilles K (2003) AMPA, kainate, and NMDA receptor densities in the hippocampus of untreated male rats and females in estrus and diestrus. J Comp Neurol 459(4):468–474. doi:10.1002/cne.10638

    Article  CAS  PubMed  Google Scholar 

  61. Damborsky JC, Winzer-Serhan UH (2012) Effects of sex and chronic neonatal nicotine treatment on Na(2)(+)/K(+)/Cl(-) co-transporter 1, K(+)/Cl(-) co-transporter 2, brain-derived neurotrophic factor, NMDA receptor subunit 2A and NMDA receptor subunit 2B mRNA expression in the postnatal rat hippocampus. Neuroscience 225:105–117. doi:10.1016/j.neuroscience.2012.09.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sato D, Lionel AC, Leblond CS, Prasad A, Pinto D, Walker S, O'Connor I, Russell C, Drmic IE, Hamdan FF, Michaud JL, Endris V, Roeth R, Delorme R, Huguet G, Leboyer M, Rastam M, Gillberg C, Lathrop M, Stavropoulos DJ, Anagnostou E, Weksberg R, Fombonne E, Zwaigenbaum L, Fernandez BA, Roberts W, Rappold GA, Marshall CR, Bourgeron T, Szatmari P, Scherer SW (2012) SHANK1 Deletions in males with autism spectrum disorder. Am J Hum Genet 90(5):879–887. doi:10.1016/j.ajhg.2012.03.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Alonso-Nanclares L, Gonzalez-Soriano J, Rodriguez JR, DeFelipe J (2008) Gender differences in human cortical synaptic density. Proc Natl Acad Sci U S A 105(38):14615–14619. doi:10.1073/pnas.0803652105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Forlano PM, Woolley CS (2010) Quantitative analysis of pre- and postsynaptic sex differences in the nucleus accumbens. J Comp Neurol 518(8):1330–1348. doi:10.1002/cne.22279

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Kurian JR, Forbes-Lorman RM, Auger AP (2007) Sex difference in mecp2 expression during a critical period of rat brain development. Epigenetics Off J DNA Methylation Soc 2(3):173–178

    Article  Google Scholar 

  66. Aber KM, Nori P, MacDonald SM, Bibat G, Jarrar MH, Kaufmann WE (2003) Methyl-CpG-binding protein 2 is localized in the postsynaptic compartment: an immunochemical study of subcellular fractions. Neuroscience 116(1):77–80

    Article  CAS  PubMed  Google Scholar 

  67. Maliszewska-Cyna E, Bawa D, Eubanks JH (2010) Diminished prevalence but preserved synaptic distribution of N-methyl-d-aspartate receptor subunits in the methyl CpG binding protein 2(MeCP2)-null mouse brain. Neuroscience 168(3):624–632. doi:10.1016/j.neuroscience.2010.03.065

    Article  CAS  PubMed  Google Scholar 

  68. Nguyen MV, Du F, Felice CA, Shan X, Nigam A, Mandel G, Robinson JK, Ballas N (2012) MeCP2 is critical for maintaining mature neuronal networks and global brain anatomy during late stages of postnatal brain development and in the mature adult brain. J Neurosci 32(29):10021–10034. doi:10.1523/JNEUROSCI. 1316-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Durand S, Patrizi A, Quast KB, Hachigian L, Pavlyuk R, Saxena A, Carninci P, Hensch TK, Fagiolini M (2012) NMDA receptor regulation prevents regression of visual cortical function in the absence of Mecp2. Neuron 76(6):1078–1090. doi:10.1016/j.neuron.2012.12.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Blackman MP, Djukic B, Nelson SB, Turrigiano GG (2012) A critical and cell-autonomous role for MeCP2 in synaptic scaling up. J Neurosci 32(39):13529–13536. doi:10.1523/JNEUROSCI. 3077-12.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. McGraw CM, Samaco RC, Zoghbi HY (2011) Adult neural function requires MeCP2. Science 333(6039):186. doi:10.1126/science.1206593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J, Zoghbi HY (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320(5880):1224–1229. doi:10.1126/science.1153252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Zhang L, He J, Jugloff DG, Eubanks JH (2008) The MeCP2-null mouse hippocampus displays altered basal inhibitory rhythms and is prone to hyperexcitability. Hippocampus 18(3):294–309. doi:10.1002/hipo.20389

    Article  CAS  PubMed  Google Scholar 

  74. Weng SM, McLeod F, Bailey ME, Cobb SR (2011) Synaptic plasticity deficits in an experimental model of rett syndrome: long-term potentiation saturation and its pharmacological reversal. Neuroscience 180:314–321. doi:10.1016/j.neuroscience.2011.01.061

    Article  CAS  PubMed  Google Scholar 

  75. Martin HG, Manzoni OJ (2014) Late onset deficits in synaptic plasticity in the valproic acid rat model of autism. Front Cell Neurosci 8:23. doi:10.3389/fncel.2014.00023

    PubMed  PubMed Central  Google Scholar 

  76. Maezawa I, Jin LW (2010) Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate. J Neurosci 30(15):5346–5356. doi:10.1523/JNEUROSCI. 5966-09.2010

    Article  CAS  PubMed  Google Scholar 

  77. Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, Thadani A, Squinto SP, Yancopoulos GD, Lindsay RM (1995) A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature 374(6521):450–453. doi:10.1038/374450a0

    Article  CAS  PubMed  Google Scholar 

  78. Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736. doi:10.1146/annurev.neuro.24.1.677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nelson KB, Grether JK, Croen LA, Dambrosia JM, Dickens BF, Jelliffe LL, Hansen RL, Phillips TM (2001) Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Ann Neurol 49(5):597–606

    Article  CAS  PubMed  Google Scholar 

  80. Miyazaki K, Narita N, Sakuta R, Miyahara T, Naruse H, Okado N, Narita M (2004) Serum neurotrophin concentrations in autism and mental retardation: a pilot study. Brain Dev 26(5):292–295. doi:10.1016/S0387-7604(03)00168-2

    Article  PubMed  Google Scholar 

  81. Perry EK, Lee ML, Martin-Ruiz CM, Court JA, Volsen SG, Merrit J, Folly E, Iversen PE, Bauman ML, Perry RH, Wenk GL (2001) Cholinergic activity in autism: abnormalities in the cerebral cortex and basal forebrain. Am J Psychiatr 158(7):1058–1066

    Article  CAS  PubMed  Google Scholar 

  82. Li W, Pozzo-Miller L (2013) BDNF deregulation in Rett syndrome. Neuropharmacology. doi:10.1016/j.neuropharm.2013.03.024

    Google Scholar 

  83. Klein ME, Lioy DT, Ma L, Impey S, Mandel G, Goodman RH (2007) Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat Neurosci 10(12):1513–1514. doi:10.1038/nn2010

    Article  CAS  PubMed  Google Scholar 

  84. Chang Q, Khare G, Dani V, Nelson S, Jaenisch R (2006) The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron 49(3):341–348. doi:10.1016/j.neuron.2005.12.027

    Article  CAS  PubMed  Google Scholar 

  85. Yazdani M, Deogracias R, Guy J, Poot RA, Bird A, Barde YA (2012) Disease modeling using embryonic stem cells: MeCP2 regulates nuclear size and RNA synthesis in neurons. Stem Cells 30(10):2128–2139. doi:10.1002/stem.1180

    Article  CAS  PubMed  Google Scholar 

  86. De Meyer T, Rietzschel ER, De Buyzere ML, De Bacquer D, Van Criekinge W, De Backer GG, Gillebert TC, Van Oostveldt P, Bekaert S, Asklepios I (2007) Paternal age at birth is an important determinant of offspring telomere length. Hum Mol Genet 16(24):3097–3102. doi:10.1093/hmg/ddm271

    Article  PubMed  Google Scholar 

  87. Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, Jaenisch R, Greenberg ME (2003) Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302(5646):885–889. doi:10.1126/science.1086446

    Article  CAS  PubMed  Google Scholar 

  88. Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, Fan G, Sun YE (2003) DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302(5646):890–893. doi:10.1126/science.1090842

    Article  CAS  PubMed  Google Scholar 

  89. Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L, Chen WG, Lin Y, Savner E, Griffith EC, Hu L, Steen JA, Weitz CJ, Greenberg ME (2006) Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52(2):255–269. doi:10.1016/j.neuron.2006.09.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Shahbazian M, Young J, Yuva-Paylor L, Spencer C, Antalffy B, Noebels J, Armstrong D, Paylor R, Zoghbi H (2002) Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 35(2):243–254

    Article  CAS  PubMed  Google Scholar 

  91. De Filippis B, Ricceri L, Fuso A, Laviola G (2013) Neonatal exposure to low dose corticosterone persistently modulates hippocampal mineralocorticoid receptor expression and improves locomotor/exploratory behaviour in a mouse model of Rett syndrome. Neuropharmacology 68:174–183. doi:10.1016/j.neuropharm.2012.05.048

    Article  PubMed  Google Scholar 

  92. Larimore JL, Chapleau CA, Kudo S, Theibert A, Percy AK, Pozzo-Miller L (2009) Bdnf overexpression in hippocampal neurons prevents dendritic atrophy caused by Rett-associated MECP2 mutations. Neurobiol Dis 34(2):199–211. doi:10.1016/j.nbd.2008.12.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors declare no conflict of interests. This work was supported by the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (no. A120029), and the Framework of International Cooperation Program (2012K2A1A2032549) through the National Research Foundation of Korea (NRF) funded by the Korea government (MEST).

Author information

Authors and Affiliations

  1. Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University, Seoul, South Korea

    Ki Chan Kim, Chang Soon Choi, Ji-Woon Kim, Seol-Heui Han & Chan Young Shin

  2. Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Ki Chan Kim

  3. KU Open Innovation Center, Konkuk University, Seoul, South Korea

    Chang Soon Choi, Ji-Woon Kim & Chan Young Shin

  4. Department of Neuroscience, School of Medicine, Konkuk University, Seoul, South Korea

    Chang Soon Choi, Ji-Woon Kim & Chan Young Shin

  5. Department of Pharmacology, College of Pharmacy, Sahmyook University, Seoul, South Korea

    Jae Hoon Cheong

  6. Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, South Korea

    Jong Hoon Ryu

  7. Department of Pharmacology, School of Medicine and Center for Geriatric Neuroscience Research, IBST, Konkuk University, 1 Hwayang-Dong, Kwangjin-Gu, Seoul, 143-701, South Korea

    Chan Young Shin

Authors
  1. Ki Chan Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chang Soon Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ji-Woon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seol-Heui Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jae Hoon Cheong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jong Hoon Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chan Young Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chan Young Shin.

Additional information

Ki Chan Kim and Chang Soon Choi contributed equally to this work

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 319 kb)

ESM 2

(DOCX 303 kb)

ESM 3

(DOCX 18 kb)

ESM 4

(DOCX 26 kb)

ESM 5

(DOCX 23 kb)

ESM 6

(DOCX 22 kb)

ESM 7

(DOCX 22 kb)

ESM 8

(DOCX 17 kb)

ESM 9

(DOCX 18 kb)

ESM 10

(DOCX 20 kb)

ESM 11

(DOCX 21 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, K.C., Choi, C.S., Kim, JW. et al. MeCP2 Modulates Sex Differences in the Postsynaptic Development of the Valproate Animal Model of Autism. Mol Neurobiol 53, 40–56 (2016). https://doi.org/10.1007/s12035-014-8987-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-8987-z

Keywords

Search

Navigation