REVIEW

The neural circuit basis of Rett syndrome

  • Darren GOFFIN ,
  • Zhaolan (Joe) ZHOU
Expand
  • Department of Genetics, University of Pennsylvania School of Medicine, 450 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104, USA

Received date: 05 Jul 2012

Accepted date: 04 Aug 2012

Published date: 01 Oct 2012

Copyright

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg

Abstract

Rett syndrome is an Autism Spectrum Disorder caused by mutations in the gene encoding methyl-CpG binding protein (MeCP2). Following a period of normal development, patients lose learned communication and motor skills, and develop a number of symptoms including motor disturbances, cognitive impairments and often seizures. In this review, we discuss the role of MeCP2 in regulating synaptic function and how synaptic dysfunctions lead to neuronal network impairments and alterations in sensory information processing. We propose that Rett syndrome is a disorder of neural circuits as a result of non-linear accumulated dysfunction of synapses at the level of individual cell populations across multiple neurotransmitter systems and brain regions.

Cite this article

Darren GOFFIN , Zhaolan (Joe) ZHOU . The neural circuit basis of Rett syndrome[J]. Frontiers in Biology, 2012 , 7(5) : 428 -435 . DOI: 10.1007/s11515-012-1248-5

Acknowledgements

This work was supported by NIH grant NS058391(ZZ) and International Rett Syndrome Foundation (ZZ and DG). Z.Z. is a Pew Scholar in Biomedical Science.
1
Amir R E, Van den Veyver I B, Wan M, Tran C Q, Francke U, Zoghbi H Y (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet, 23(2): 185––188

DOI PMID

2
Armstrong D D (2005). Neuropathology of Rett syndrome. J Child Neurol, 20(9): 747–753

DOI PMID

3
Asaka Y, Jugloff D G M, Zhang L, Eubanks J H, Fitzsimonds R M (2006). Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. Neurobiol Dis, 21(1): 217–227

DOI PMID

4
Bader G G, Witt-Engerström I, Hagberg B (1989). Neurophysiological findings in the Rett syndrome, II: Visual and auditory brainstem, middle and late evoked responses. Brain Dev, 11(2): 110–114

DOI PMID

5
Belichenko N P, Belichenko P V, Mobley W C (2009a). Evidence for both neuronal cell autonomous and nonautonomous effects of methyl-CpG-binding protein 2 in the cerebral cortex of female mice with Mecp2 mutation. Neurobiol Dis, 34(1): 71–77

DOI PMID

6
Belichenko P V, Wright E E, Belichenko N P, Masliah E, Li H H, Mobley W C, Francke U (2009b). Widespread changes in dendritic and axonal morphology in Mecp2-mutant mouse models of Rett syndrome: evidence for disruption of neuronal networks. J Comp Neurol, 514(3): 240–258

DOI PMID

7
Calfa G, Hablitz J J, 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 PMID

8
Chahrour M, Jung S Y, Shaw C, Zhou X, Wong S T C, Qin J, Zoghbi H Y (2008). MeCP2, a key contributor to neurological disease, activates and represses transcription. Science, 320(5880): 1224–1229

DOI PMID

9
Chahrour M, Zoghbi H Y (2007). The story of Rett syndrome: from clinic to neurobiology. Neuron, 56(3): 422–437

DOI PMID

10
Chao H T, Chen H, Samaco R C, Xue M, Chahrour M, Yoo J, Neul J L, Gong S, Lu H C, Heintz N, Ekker M, Rubenstein J L, Noebels J L, Rosenmund C, Zoghbi H Y (2010). Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature, 468(7321): 263–269

DOI PMID

11
Chao H T, Zoghbi H Y, Rosenmund C (2007). MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron, 56(1): 58–65

DOI PMID

12
Chen R Z, 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(3): 327–331

DOI PMID

13
Chen W G, Chang Q, Lin Y, Meissner A, West A E, Griffith E C, Jaenisch R, Greenberg M E (2003). Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science, 302(5646): 885–889

DOI PMID

14
Cheval H, Guy J, Merusi C, De Sousa D, Selfridge J, Bird A(2012). Postnatal inactivation reveals enhanced requirement for MeCP2 at distinct age windows. Hum Mol Genet, 21(17): 3806–3814

DOI

15
Cohen S, Gabel H W, Hemberg M, Hutchinson A N, Sadacca L A, Ebert D H, Harmin D A, Greenberg R S, Verdine V K, Zhou Z, Wetsel W C, West A E, Greenberg M E (2011). Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function. Neuron, 72(1): 72–85

DOI PMID

16
Collins A L, Levenson J M, Vilaythong A P, Richman R, Armstrong D L, Noebels J L, David Sweatt J, Zoghbi H Y (2004). Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum Mol Genet, 13(21): 2679–2689

DOI PMID

17
Cull-Candy S, Brickley S, Farrant M (2001). NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol, 11(3): 327–335

DOI PMID

18
D’Cruz J A, Wu C, Zahid T, El-Hayek Y, Zhang L, Eubanks J H (2010). Alterations of cortical and hippocampal EEG activity in MeCP2-deficient mice. Neurobiol Dis, 38(1): 8–16

DOI PMID

19
Dani V S, Chang Q, Maffei A, Turrigiano G G, Jaenisch R, Nelson S B (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(35): 12560–12565

DOI PMID

20
Dani V S, Nelson S B (2009). Intact long-term potentiation but reduced connectivity between neocortical layer 5 pyramidal neurons in a mouse model of Rett syndrome. J Neurosci, 29(36): 11263–11270

DOI PMID

21
Derecki N C, Cronk J C, Lu Z, Xu E, Abbott S B G, Guyenet P G, Kipnis J (2012). Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature, 484(7392): 105–109

DOI PMID

22
Fyffe S L, Neul J L, Samaco R C, Chao H T, Ben-Shachar S, Moretti P, McGill B E, Goulding E H, Sullivan E, Tecott L H, Zoghbi H Y (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(6): 947–958

DOI PMID

23
Gandal M J, Edgar J C, Klook K, Siegel S J (2011). Gamma synchrony: Towards a translational biomarker for the treatment-resistant symptoms of schizophrenia. Neuropharmacology, 62(3): 1504–1518

24
Gantz S C, Ford C P, Neve K A, Williams J T (2011). Loss of Mecp2 in substantia nigra dopamine neurons compromises the nigrostriatal pathway. J Neurosci, 31(35): 12629–12637

DOI PMID

25
Gemelli T, Berton O, Nelson E D, Perrotti L I, Jaenisch R, Monteggia L M (2006). Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice. Biol Psychiatry, 59(5): 468–476

DOI PMID

26
Goffin D, Allen M, Zhang L, Amorim M, Wang I T J, Reyes A R S, Mercado-Berton A, Ong C, Cohen S, Hu L, Blendy J A, Carlson G C, Siegel S J, Greenberg M E, Zhou Z (2012). Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses. Nat Neurosci, 15(2): 274–283

DOI PMID

27
Guy J, Gan J, Selfridge J, Cobb S, Bird A (2007). Reversal of neurological defects in a mouse model of Rett syndrome. Science, 315(5815): 1143–1147

DOI PMID

28
Guy J, Hendrich B, Holmes M, Martin J E, Bird A (2001). A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet, 27(3): 322–326

DOI PMID

29
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 PMID

30
Jones P L, Veenstra G J, Wade P A, Vermaak D, Kass S U, Landsberger N, Strouboulis J, Wolffe A P (1998). Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet, 19(2): 187–191

DOI PMID

31
Kishi N, Macklis J D (2004). MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol Cell Neurosci, 27(3): 306–321

DOI PMID

32
Lewis J D, Meehan R R, Henzel W J, Maurer-Fogy I, Jeppesen P, Klein F, Bird A (1992). Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell, 69(6): 905–914

DOI PMID

33
Lioy D T, Garg S K, Monaghan C E, Raber J, Foust K D, Kaspar B K, Hirrlinger P G, Kirchhoff F, Bissonnette J M, Ballas N, Mandel G (2011). A role for glia in the progression of Rett’s syndrome. Nature, 475(7357): 497–500

DOI PMID

34
Lonetti G, Angelucci A, Morando L, Boggio E M, Giustetto M, Pizzorusso T (2010). Early environmental enrichment moderates the behavioral and synaptic phenotype of MeCP2 null mice. Biol Psychiatry, 67(7): 657–665

DOI PMID

35
Marchetto M C N, Carromeu C, Acab A, Yu D, Yeo G W, Mu Y, Chen G, Gage F H, Muotri A R (2010). A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell, 143(4): 527–539

DOI PMID

36
McGraw C M, Samaco R C, Zoghbi H Y (2011). Adult neural function requires MeCP2. Science, 333(6039): 186

DOI PMID

37
Medrihan L, Tantalaki E, Aramuni G, Sargsyan V, Dudanova I, Missler M, Zhang W (2008). Early defects of GABAergic synapses in the brain stem of a MeCP2 mouse model of Rett syndrome. J Neurophysiol, 99(1): 112–121

DOI PMID

38
Moretti P, Levenson J M, Battaglia F, Atkinson R, Teague R, Antalffy B, Armstrong D, Arancio O, Sweatt J D, Zoghbi H Y (2006). Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J Neurosci, 26(1): 319–327

DOI PMID

39
Na E S, Nelson E D, Adachi M, Autry A E, Mahgoub M A, Kavalali E T, Monteggia L M (2012). A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission. J Neurosci, 32(9): 3109–3117

DOI PMID

40
Nan X, Campoy F J, Bird A (1997). MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell, 88(4): 471–481

DOI PMID

41
Nan X, Ng H H, Johnson C A, Laherty C D, Turner B M, Eisenman R N, Bird A (1998). Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature, 393(6683): 386–389

DOI PMID

42
Neul J L, Kaufmann W E, Glaze D G, Christodoulou J, Clarke A J, Bahi-Buisson N, Leonard H, Bailey M E S, Schanen N C, Zappella M, Renieri A, Huppke P, Percy A K, and the RettSearch Consortium (2010). Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol, 68(6): 944–950

DOI PMID

43
Noutel J, Hong Y K, Leu B, Kang E, Chen C (2011). Experience-dependent retinogeniculate synapse remodeling is abnormal in MeCP2-deficient mice. Neuron, 70(1): 35–42

DOI PMID

44
Qiu Z, Sylwestrak E L, Lieberman D N, Zhang Y, Liu X Y, Ghosh A (2012). The Rett syndrome protein MeCP2 regulates synaptic scaling. J Neurosci, 32(3): 989–994

DOI PMID

45
Samaco R C, Mandel-Brehm C, Chao H T, Ward C S, Fyffe-Maricich S L, Ren J, Hyland K, Thaller C, Maricich S M, Humphreys P, Greer J J, Percy A, Glaze D G, Zoghbi H Y, Neul J L (2009). Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities. Proc Natl Acad Sci USA, 106(51): 21966–21971

DOI PMID

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(2): 243–254

DOI PMID

47
Skene P J, Illingworth R S, Webb S, Kerr A R W, James K D, Turner D J, Andrews R, Bird A P (2010). Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol Cell, 37(4): 457–468

DOI PMID

48
Stauder J E A, Smeets E E J, van Mil S G M, Curfs L G M (2006). The development of visual- and auditory processing in Rett syndrome: an ERP study. Brain Dev, 28(8): 487–494

DOI PMID

49
Szulwach K E, Li X, Smrt R D, Li Y, Luo Y, Lin L, Santistevan N J, Li W, Zhao X, Jin P (2010). Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J Cell Biol, 189(1): 127–141

DOI PMID

50
Taneja P, Ogier M, Brooks-Harris G, Schmid D A, Katz D M, Nelson S B (2009). Pathophysiology of locus ceruleus neurons in a mouse model of Rett syndrome. J Neurosci, 29(39): 12187–12195

DOI PMID

51
Tropea D, Giacometti E, Wilson N R, Beard C, McCurry C, Fu D D, Flannery R, Jaenisch R, Sur M (2009). Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci USA, 106(6): 2029–2034

DOI PMID

52
Uhlhaas P J, Singer W (2010). Abnormal neural oscillations and synchrony in schizophrenia. Nat Rev Neurosci, 11(2): 100–113

DOI PMID

53
van Zundert B, Yoshii A, Constantine-Paton M (2004). Receptor compartmentalization and trafficking at glutamate synapses: a developmental proposal. Trends Neurosci, 27(7): 428–437

DOI PMID

54
Ward C S, Arvide E M, Huang T W, Yoo J, Noebels J L, Neul J L (2011). MeCP2 is critical within HoxB1-derived tissues of mice for normal lifespan. J Neurosci, 31(28): 10359–10370

DOI PMID

55
Weng S M, McLeod F, Bailey M E S, Cobb S R (2011). Synaptic plasticity deficits in an experimental model of Rett syndrome: long-term potentiation saturation and its pharmacological reversal. Neuroscience, 180: 314–321

56
Wood L, Gray N W, Zhou Z, Greenberg M E, Shepherd G M G (2009). Synaptic circuit abnormalities of motor-frontal layer 2/3 pyramidal neurons in an RNA interference model of methyl-CpG-binding protein 2 deficiency. J Neurosci, 29(40): 12440–12448

DOI PMID

57
Wood L, Shepherd G M G (2010). Synaptic circuit abnormalities of motor-frontal layer 2/3 pyramidal neurons in a mutant mouse model of Rett syndrome. Neurobiol Dis, 38(2): 281–287

DOI PMID

58
Wu H, Tao J, Chen P J, Shahab A, Ge W, Hart R P, Ruan X, Ruan Y, Sun Y E (2010). Genome-wide analysis reveals methyl-CpG-binding protein 2-dependent regulation of microRNAs in a mouse model of Rett syndrome. Proc Natl Acad Sci USA, 107(42): 18161–18166

DOI PMID

59
Young J I, Hong E P, Castle J C, Crespo-Barreto J, Bowman A B, Rose M F, Kang D, Richman R, Johnson J M, Berget S, Zoghbi H Y (2005). Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc Natl Acad Sci USA, 102(49): 17551–17558

DOI PMID

60
Zhang Z W, Zak J D, Liu H (2010). MeCP2 is required for normal development of GABAergic circuits in the thalamus. J Neurophysiol, 103(5): 2470–2481

DOI PMID

61
Zhou Z, Hong E J, Cohen S, Zhao W N, Ho H Y H, Schmidt L, Chen W G, Lin Y, Savner E, Griffith E C, Hu L, Steen J A, Weitz C J, Greenberg M E (2006). Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron, 52(2): 255–269

DOI PMID

62
Zoghbi H Y (2003). Postnatal neurodevelopmental disorders: meeting at the synapse?Science, 302(5646): 826–830

DOI PMID

Outlines

/