Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome

被引:256
作者
Asaka, Y
Jugloff, DGM
Zhang, LA
Eubanks, JH
Fitzsimonds, RM
机构
[1] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA
[2] Univ Toronto, Toronto Western Res Inst, Div Cellular & Mol Biol, Toronto, ON M5T 2S8, Canada
关键词
LTP; LTD; mental retardation;
D O I
10.1016/j.nbd.2005.07.005
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Rett syndrome is an X-linked neurodevelopmental disorder caused by mutations in the gene encoding the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2). Here we demonstrate that the Meep2-null mouse model of Rett syndrome shows an age-dependent impairment in hippocampal CA1 long-term potentiation induced by tetanic or theta-burst stimulation. Long-term depression induced by repetitive low-frequency stimulation is also absent in behaviorally symptomatic Mecp2-null mice. Immunoblot analyses from behaviorally symptomatic Meep2-null mice reveal altered expression of N-methyl-D-aspartate receptor subunits NR2A and NR2B. Presynaptic function is also affected, as demonstrated by a significant reduction in paired-pulse facilitation. Interestingly, the properties of basal neurotransmission are normal in the Meep2-null mice, consistent with our observations that the levels of expression of synaptic and cytoskeletal proteins, including glutamate receptor subunits GluR1 and GluR2, PSD95, synaptophysin-1, synaptobrevin-2, synaptotagmin-1, MAP2, beta III-tubulin and NF200, are not significantly altered. Together, these data provide the first evidence that the loss of Meep2 expression is accompanied by age-dependent alterations in excitatory synaptic plasticity that are likely to contribute to the cognitive and functional deficits underlying Rett syndrome. (c) 2005 Elsevier Inc. All rights reserved.
引用
收藏
页码:217 / 227
页数:11
相关论文
共 36 条
[1]   Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 [J].
Amir, RE ;
Van den Veyver, IB ;
Wan, M ;
Tran, CQ ;
Francke, U ;
Zoghbi, HY .
NATURE GENETICS, 1999, 23 (02) :185-188
[2]   Rett syndrome neuropathology review 2000 [J].
Armstrong, DD .
BRAIN & DEVELOPMENT, 2001, 23 :S72-S76
[3]   Neuropathology of Rett syndrome [J].
Armstrong, DD .
MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS, 2002, 8 (02) :72-76
[4]   RETT-SYNDROME - 3-D CONFOCAL MICROSCOPY OF CORTICAL PYRAMIDAL DENDRITES AND AFFERENTS [J].
BELICHENKO, PV ;
OLDFORS, A ;
HAGBERG, B ;
DAHLSTROM, A .
NEUROREPORT, 1994, 5 (12) :1509-1513
[5]  
Blue ME, 1999, ANN NEUROL, V45, P541, DOI 10.1002/1531-8249(199904)45:4<541::AID-ANA21>3.0.CO
[6]  
2-2
[7]   Altered development of glutamate and GABA receptors in the basal ganglia of girls with Rett syndrome [J].
Blue, ME ;
Naidu, S ;
Johnston, MV .
EXPERIMENTAL NEUROLOGY, 1999, 156 (02) :345-352
[8]  
Chen GQ, 1999, J NEUROSCI, V19, P7983
[9]   Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice [J].
Chen, RZ ;
Akbarian, S ;
Tudor, M ;
Jaenisch, R .
NATURE GENETICS, 2001, 27 (03) :327-331
[10]   Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2 [J].
Chen, WG ;
Chang, Q ;
Lin, YX ;
Meissner, A ;
West, AE ;
Griffith, EC ;
Jaenisch, R ;
Greenberg, ME .
SCIENCE, 2003, 302 (5646) :885-889