MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number.
MeCP2 is a transcriptional repressor critical for normal neurological function. Prior studies demonstrated that either loss or doubling of MeCP2 results in postnatal neurodevelopmental disorders. To understand the impact of MeCP2 expression on neuronal function, we studied the synaptic properties of individual neurons from mice that either lack or express twice the normal levels of MeCP2. Hippocampal glutamatergic neurons that lack MeCP2 display a 46% reduction in synaptic response, whereas neurons with doubling of MeCP2 exhibit a 2-fold enhancement in synaptic response. Further analysis shows that these changes were primarily due to the number of synapses formed. These results reveal that MeCP2 is a key rate-limiting factor in regulating glutamatergic synapse formation in early postnatal development and that changes in excitatory synaptic strength may underlie global network alterations in neurological disorders due to altered MeCP2 levels.
Chao
Hsiao-Tuan
HT
Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Zoghbi
Huda Y
HY
Rosenmund
Christian
C
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology; D000076122:Disks Large Homolog 4 Protein; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D018507:Gene Expression Regulation, Developmental; D018698:Glutamic Acid / Q000378:metabolism*; D051528:Guanylate Kinases; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D013569:Synapses / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D050496:Vesicular Glutamate Transport Proteins / Q000378:metabolism
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C497393:Mecp2 protein, mouse; D008565:Membrane Proteins; D051783:Methyl-CpG-Binding Protein 2; D050496:Vesicular Glutamate Transport Proteins; D018698:Glutamic Acid; D051528:Guanylate Kinases