Excitatory synapses are stronger in the hippocampus of Rett syndrome mice due to altered synaptic trafficking of AMPA-type glutamate receptors.
Deficits in long-term potentiation (LTP) at central excitatory synapses are thought to contribute to cognitive impairments in neurodevelopmental disorders associated with intellectual disability and autism. Using the methyl-CpG-binding protein 2 (Mecp2) knockout (KO) mouse model of Rett syndrome, we show that naïve excitatory synapses onto hippocampal pyramidal neurons of symptomatic mice have all of the hallmarks of potentiated synapses. Stronger Mecp2 KO synapses failed to undergo LTP after either theta-burst afferent stimulation or pairing afferent stimulation with postsynaptic depolarization. On the other hand, basal synaptic strength and LTP were not affected in slices from younger presymptomatic Mecp2 KO mice. Furthermore, spine synapses in pyramidal neurons from symptomatic Mecp2 KO are larger and do not grow in size or incorporate GluA1 subunits after electrical or chemical LTP. Our data suggest that LTP is occluded in Mecp2 KO mice by already potentiated synapses. The higher surface levels of GluA1-containing receptors are consistent with altered expression levels of proteins involved in AMPA receptor trafficking, suggesting previously unidentified targets for therapeutic intervention for Rett syndrome and other MECP2-related disorders.
['Li|Wei|W|', 'Xu|Xin|X|', 'Pozzo-Miller|Lucas|L|http://orcid.org/0000-0001-6085-5527']
D000818:Animals D000074288:Discs Large Homolog 1 Protein D004195:Disease Models, Animal D005260:Female D051528:Guanylate Kinases D006624:Hippocampus D017774:Long-Term Potentiation D008297:Male D008565:Membrane Proteins D051783:Methyl-CpG-Binding Protein 2 D008810:Mice, Inbred C57BL D018345:Mice, Knockout D009474:Neurons D021381:Protein Transport D018091:Receptors, AMPA D016194:Receptors, N-Methyl-D-Aspartate D015518:Rett Syndrome D013569:Synapses D033921:Vesicular Transport Proteins
LTP MeCP2 GluA1 CA1 dendritic spine