Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome.
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 Mecp2-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 Mecp2-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 Mecp2-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, betaIII-tubulin and NF200, are not significantly altered. Together, these data provide the first evidence that the loss of Mecp2 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.
Asaka
Yukiko
Y
Department of Cellular and Molecular Physiology, Yale University School of Medicine, PO Box 208026, New Haven, CT 06520, USA.
Jugloff
Denis G M
DG
Zhang
Liang
L
Eubanks
James H
JH
Fitzsimonds
Reiko Maki
RM
D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006624:Hippocampus / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009473:Neuronal Plasticity / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015518:Rett Syndrome / Q000378:metabolism / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000502:physiology; D013826:Theta Rhythm
D003598:Cytoskeletal Proteins; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D016194:Receptors, N-Methyl-D-Aspartate