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Analysis of MeCP2 Function in the CNS

  • Ege T. Kavalali
  • Lisa M. Monteggia
Chapter
Part of the Research and Perspectives in Neurosciences book series (NEUROSCIENCE)

Abstract

Mutations in the methyl-CpG-binding protein (MeCP2) have been linked as the causative factor to Rett Syndrome (RTT). The MECP2 gene encodes a DNA binding protein that binds to methylated cytosines in the mammalian genome. The disease-causing mutations found in RTT patients are predicted to result in the loss of function of MeCP2 that then results in genes turned on in an inappropriate manner. Over the past several years, our group has examined the role of MeCP2 in complex behavior as well as neurotransmission. Our behavioral analysis has shown that the forebrain-specific Mecp2 loss-of-function in mice could recapitulate several behavioral and neurological deficits associated with RTT. Interestingly, we could also show that brain region-specific Mecp2 loss-of-function, such as selective knock down of MeCP2 in basolateral amygdala, could trigger a subset of RTT phenotypes such as an increased anxiety-like behavior and deficits in cue-dependent fear conditioning. We have also demonstrated that loss of MeCP2 in neurons results in a decrease in spontaneous excitatory synaptic transmission coupled with an increase in action potential-driven excitatory drive. The combined effort of behavioral and synaptic analysis of MeCP2-associated phenotypes will not only open new avenues for understanding neuronal circuit abnormalities associated with neurodevelopmental disorders but also elucidate potential targets for addressing the pathophysiology of several intractable neuropsychiatric disorders.

Keywords

Rett Syndrome Excitatory Synaptic Transmission MECP2 Gene Juvenile Mouse MeCP2 Expression 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Adachi M, Barrot M, Autry AE, Theobald D, Monteggia LM (2008) Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy. Biol Psychiat 63:642–649CrossRefPubMedGoogle Scholar
  2. Adachi M, Autry AE, Covington HE 3rd, Monteggia LM (2009) MeCP2-mediated transcription repression in the basolateral amygdala may underlie heightened anxiety in a mouse model of Rett syndrome. J Neurosci 29:4218–4227CrossRefPubMedGoogle Scholar
  3. Amir RE, Zoghbi HY (2000) Rett syndrome: methyl-CpG-binding protein 2 mutations and phenotype-genotype correlations. Am J Med Genet 97:147–152CrossRefPubMedGoogle Scholar
  4. 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 23:185–188CrossRefPubMedGoogle Scholar
  5. Asaka Y, Jugloff DG, Zhang L, Eubanks JH, Fitzsimonds RM (2006) Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. Neurobiol Dis 21:217–227CrossRefPubMedGoogle Scholar
  6. Atasoy D, Ertunc M, Moulder KL, Blackwell J, Chung C, Su J, Kavalali ET (2008) Spontaneous and evoked glutamate release activates two populations of NMDA receptors with limited overlap. J Neurosci 28:10151–10166CrossRefPubMedGoogle Scholar
  7. Auerbach W, Hurlbert MS, Hilditch-Maguire P, Wadghiri YZ, Wheeler VC, Cohen SI, Joyner AL, MacDonald ME, Turnbull DH (2001) The HD mutation causes progressive lethal neurological disease in mice expressing reduced levels of huntingtin. Hum Mol Genet 10:2515–2523CrossRefPubMedGoogle Scholar
  8. Ballas N, Lioy DT, Grunseich C, Mandel G (2009) Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. Nat Neurosci 12:311–317CrossRefPubMedGoogle Scholar
  9. Ballestar E, Yusufzai TM, Wolffe AP (2000) Effects of Rett syndrome mutations of the methyl-CpG binding domain of the transcriptional repressor MeCP2 on selectivity for association with methylated DNA. Biochemistry 39:7100–7106CrossRefPubMedGoogle Scholar
  10. Bienvenu T, Carrie A, de Roux N, Vinet MC, Jonveaux P, Couvert P, Villard L, Arzimanoglou A, Beldjord C, Fontes M, Tardieu M, Chelly J (2000) MECP2 mutations account for most cases of typical forms of Rett syndrome. Hum Mol Genet 9:1377–1384CrossRefPubMedGoogle Scholar
  11. Campeau S, Davis M (1995) Involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli. J Neurosci 15:2301–2311PubMedGoogle Scholar
  12. Carney RM, Wolpert CM, Ravan SA, Shahbazian M, Ashley-Koch A, Cuccaro ML, Vance JM, Pericak-Vance MA (2003) Identification of MeCP2 mutations in a series of females with autistic disorder. Pediatr Neurol 28:205–211CrossRefPubMedGoogle Scholar
  13. Chahrour M, Zoghbi HY (2007) The story of Rett syndrome: from clinic to neurobiology. Neuron 56:422–437CrossRefPubMedGoogle Scholar
  14. 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 320:1224–1229CrossRefPubMedGoogle Scholar
  15. Chao HT, Zoghbi HY, Rosenmund C (2007) MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56:58–65CrossRefPubMedGoogle Scholar
  16. 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 468:263–269CrossRefPubMedGoogle Scholar
  17. Chen RZ, Akbarian S, Tudor M, Jaenisch R (2001) Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat Genet 27:327–331CrossRefPubMedGoogle Scholar
  18. Cohen S, Gabel HW, Hemberg M, Hutchinson AN, Sadacca LA, Ebert DH, Harmin DA, Greenberg RS, Verdine VK, Zhou Z, Wetsel WC, West AE, Greenberg ME (2011) Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function. Neuron. 72(1):72–85Google Scholar
  19. Dani VS, Chang Q, Maffei A, Turrigiano GG, Jaenisch R, Nelson SB (2005) Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc Natl Acad Sci USA 102:12560–12565CrossRefPubMedGoogle Scholar
  20. Davis M, Shi C (2000) The amygdala. Curr Biol 10:R131CrossRefPubMedGoogle Scholar
  21. Francke U (2006) Mechanisms of disease: neurogenetics of MeCP2 deficiency. Nat Clin Pract Neurol 2:212–221CrossRefPubMedGoogle Scholar
  22. Fredj NB, Burrone J (2009) A resting pool of vesicles is responsible for spontaneous vesicle fusion at the synapse. Nat Neurosci 12:751–758CrossRefPubMedGoogle Scholar
  23. Fyffe SL, Neul JL, Samaco RC, Chao HT, Ben-Shachar S, Moretti P, McGill BE, Goulding EH, Sullivan E, Tecott LH, Zoghbi HY (2008) Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress. Neuron 59:947–958CrossRefPubMedGoogle Scholar
  24. Gemelli T, Berton O, Nelson ED, Perrotti LI, Jaenisch R, Monteggia LM (2006) Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice. Biol Psychiat 59:468–476CrossRefPubMedGoogle Scholar
  25. Glaze DG (2005) Neurophysiology of Rett syndrome. J Child Neurol 20:740–746PubMedGoogle Scholar
  26. Guidetti P, Charles V, Chen EY, Reddy PH, Kordower JH, Whetsell WO Jr, Schwarcz R, Tagle DA (2001) Early degenerative changes in transgenic mice expressing mutant huntingtin involve dendritic abnormalities but no impairment of mitochondrial energy production. Exp Neurol 169:340–350CrossRefPubMedGoogle Scholar
  27. Guy J, Hendrich B, Holmes M, Martin JE, Bird A (2001) A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 27:322–326CrossRefPubMedGoogle Scholar
  28. 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 14:471–479CrossRefPubMedGoogle Scholar
  29. Huppke P, Laccone F, Kramer N, Engel W, Hanefeld F (2000) Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum Mol Genet 9:1369–1375CrossRefPubMedGoogle Scholar
  30. Kishi N, Macklis JD (2004) MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol Cell Neurosci 27:306–321CrossRefPubMedGoogle Scholar
  31. Klose RJ, Sarraf SA, Schmiedeberg L, McDermott SM, Stancheva I, Bird AP (2005) DNA binding selectivity of MeCP2 due to a requirement for A/T sequences adjacent to methyl-CpG. Mol Cell 19:667–678CrossRefPubMedGoogle Scholar
  32. Lam CW, Yeung WL, Ko CH, Poon PM, Tong SF, Chan KY, Lo IF, Chan LY, Hui J, Wong V, Pang CP, Lo YM, Fok TF (2000) Spectrum of mutations in the MECP2 gene in patients with infantile autism and Rett syndrome. J Med Genet 37:E41CrossRefPubMedGoogle Scholar
  33. LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184CrossRefPubMedGoogle Scholar
  34. LeDoux J (2007) The amygdala. Curr Biol 17:R868–874CrossRefPubMedGoogle Scholar
  35. Maren S (2001) Neurobiology of Pavlovian fear conditioning. Annu Rev Neurosci 24:897–931CrossRefPubMedGoogle Scholar
  36. Maren S, Fanselow MS (1995) Synaptic plasticity in the basolateral amygdala induced by hippocampal formation stimulation in vivo. J Neurosci 15:7548–7564PubMedGoogle Scholar
  37. Matarazzo V, Cohen D, Palmer AM, Simpson PJ, Khokhar B, Pan SJ, Ronnett GV (2004) The transcriptional repressor Mecp2 regulates terminal neuronal differentiation. Mol Cell Neurosci 27:44–58CrossRefPubMedGoogle Scholar
  38. Nelson ED, Kavalali ET, Monteggia LM (2006) MeCP2-dependent transcriptional repression regulates excitatory neurotransmission. Curr Biol 16:710–716CrossRefPubMedGoogle Scholar
  39. Nelson ED, Bal M, Kavalali ET, Monteggia LM (2011) Selective impact of MeCP2 and associated histone deacetylases on the dynamics of evoked excitatory neurotransmission. J Neurophys 106:193–201CrossRefGoogle Scholar
  40. Rainnie DG, Bergeron R, Sajdyk TJ, Patil M, Gehlert DR, Shekhar A (2004) Corticotrophin releasing factor-induced synaptic plasticity in the amygdala translates stress into emotional disorders. J Neurosci 24:3471–3479CrossRefPubMedGoogle Scholar
  41. Ravn K, Nielsen JB, Schwartz M (2005) Mutations found within exon 1 of MECP2 in Danish patients with Rett syndrome. Clin Genet 67:532–533CrossRefPubMedGoogle Scholar
  42. Roozendaal B, Brunson KL, Holloway BL, McGaugh JL, Baram TZ (2002) Involvement of stress-released corticotropin-releasing hormone in the basolateral amygdala in regulating memory consolidation. Proc Natl Acad Sci USA 99:13908–13913CrossRefPubMedGoogle Scholar
  43. Rothwell PE (2010) Parsing spontaneous and evoked neurotransmission on both sides of the synapse. J Neurosci 30:6480–6481CrossRefPubMedGoogle Scholar
  44. Samaco RC, Mandel-Brehm C, Chao HT, Ward CS, Fyffe-Maricich SL, Ren J, Hyland K, Thaller C, Maricich SM, Humphreys P, Greer JJ, Percy A, Glaze DG, Zoghbi HY (2009) Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities. Proc Natl Acad Sci USA 106:21966–21971CrossRefPubMedGoogle Scholar
  45. Sara Y, Virmani T, Deak F, Liu X, Kavalali ET (2005) An isolated pool of vesicles recycles at rest and drives spontaneous neurotransmission. Neuron 45:563–573CrossRefPubMedGoogle Scholar
  46. 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 35:243–254CrossRefPubMedGoogle Scholar
  47. Skene PJ, Illingworth RS, Webb S, Kerr AR, James KD, Turner DJ, Andrews R, Bird AP (2010) Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol Cell. 37(4):457–68Google Scholar
  48. Sutton MA, Schuman EM (2009) Partitioning the synaptic landscape: distinct microdomains for spontaneous and spike-triggered neurotransmission. Sci Signal 2:pe19CrossRefPubMedGoogle Scholar
  49. Tate P, Skarnes W, Bird A (1996) The methyl-CpG binding protein MeCP2 is essential for embryonic development in the mouse. Nat Genet 12:205–208CrossRefPubMedGoogle Scholar
  50. Tropea D, Giacometti E, Wilson NR, Beard C, McCurry C, Fu DD, Flannery R, Jaenisch R, Sur M (2009) Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci USA 106:2029–2034CrossRefPubMedGoogle Scholar
  51. van Dellen A, Deacon R, York D, Blakemore C, Hannan AJ (2001) Anterior cingulate cortical transplantation in transgenic Huntington’s disease mice. Brain Res Bull 56:313–318CrossRefPubMedGoogle Scholar
  52. Van Esch H, Bauters M, Ignatius J, Jansen M, Raynaud M, Hollanders K, Lugtenberg D, Bienvenu T, Jensen LR, Gecz J, Moraine C, Marynen P, Fryns JP, Froyen G (2005) Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am J Hum Genet 77:442–453CrossRefPubMedGoogle Scholar
  53. Wan M, Lee SS, Zhang X, Houwink-Manville I, Song HR, Amir RE, Budden S, Naidu S, Pereira JL, Lo IF, Zoghbi HY, Schanen NC, Francke U (1999) Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am J Hum Genet 65:1520–1529CrossRefPubMedGoogle Scholar
  54. Watson P, Black G, Ramsden S, Barrow M, Super M, Kerr B, Clayton-Smith J (2001) Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein. J Med Genet 38:224–228CrossRefPubMedGoogle Scholar
  55. Wilensky AE, Schafe GE, LeDoux JE (1999) Functional inactivation of the amygdala before but not after auditory fear conditioning prevents memory formation. J Neurosci 19:RC48PubMedGoogle Scholar
  56. Yasui DH, Peddada S, Bieda MC, Vallero RO, Hogart A, Nagarajan RP, Thatcher KN, Farnham PJ, Lasalle JM (2007) Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes. Proc Natl Acad Sci USA 104:19416–19421CrossRefPubMedGoogle Scholar
  57. Ylisaukko-Oja T, Rehnstrom K, Vanhala R, Kempas E, von Koskull H, Tengström C, Mustonen A, Ounap K, Lähdetie J, Järvelä I (2005) MECP2 mutation analysis in patients with mental retardation. Am J Med Genet 132A(2):121–124CrossRefPubMedGoogle Scholar
  58. Yusufzai TM, Wolffe AP (2000) Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res 28:4172–4179CrossRefPubMedGoogle Scholar
  59. Zoghbi HY (2005) MeCP2 dysfunction in humans and mice. J Child Neurol 20:736–740PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of NeuroscienceUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Department of PsychiatryUniversity of Texas Southwestern Medical CenterDallasUSA

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