Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2.
Fragile X syndrome (FXS), the most common genetic form of mental retardation and autism, is caused by loss-of-function mutations in an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP). Neurons from patients and the mouse Fmr1 knockout (KO) model are characterized by an excess of dendritic spines, suggesting a deficit in excitatory synapse elimination. In response to neuronal activity, myocyte enhancer factor 2 (MEF2) transcription factors induce robust synapse elimination. Here, we demonstrate that MEF2 activation fails to eliminate functional or structural excitatory synapses in hippocampal neurons from Fmr1 KO mice. Similarly, inhibition of endogenous MEF2 increases synapse number in wild-type but not Fmr1 KO neurons. MEF2-dependent synapse elimination is rescued in Fmr1 KO neurons by acute postsynaptic expression of wild-type but not RNA-binding mutants of FMRP. Our results reveal that active MEF2 and FMRP function together in an acute, cell-autonomous mechanism to eliminate excitatory synapses.
Pfeiffer
Brad E
BE
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Zang
Tong
T
Wilkerson
Julia R
JR
Taniguchi
Makoto
M
Maksimova
Marina A
MA
Smith
Laura N
LN
Cowan
Christopher W
CW
Huber
Kimberly M
KM
D000818:Animals; D049229:Dendritic Spines / Q000235:genetics / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D036641:Microscopy, Fluorescence, Multiphoton; D055369:Miniature Postsynaptic Potentials / Q000235:genetics; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D009415:Nerve Net / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection
D051860:Fragile X Messenger Ribonucleoprotein 1; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D016601:RNA-Binding Proteins; C578036:Mef2a protein, mouse