MEF2 negatively regulates learning-induced structural plasticity and memory formation


Memory formation is thought to be mediated by dendritic-spine growth and restructuring. Myocyte enhancer factor 2 (MEF2) restricts spine growth in vitro, suggesting that this transcription factor negatively regulates the spine remodeling necessary for memory formation. Here we show that memory formation in adult mice was associated with changes in endogenous MEF2 levels and function. Locally and acutely increasing MEF2 function in the dentate gyrus blocked both learning-induced increases in spine density and spatial-memory formation. Increasing MEF2 function in amygdala disrupted fear-memory formation. We rescued MEF2-induced memory disruption by interfering with AMPA receptor endocytosis, suggesting that AMPA receptor trafficking is a key mechanism underlying the effects of MEF2. In contrast, decreasing MEF2 function in dentate gyrus and amygdala facilitated the formation of spatial and fear memory, respectively. These bidirectional effects indicate that MEF2 is a key regulator of plasticity and that relieving the suppressive effects of MEF2-mediated transcription permits memory formation.

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Figure 1: Memory formation was associated with inhibitory phosphorylation of MEF2 and a decrease in amount of MEF2 protein.
Figure 2: Increasing MEF2 function during training impaired formation of spatial memory.
Figure 3: Increasing MEF2 function blocked spine growth associated with memory formation.
Figure 4: Increasing MEF2 function after training impaired memory incubation.
Figure 5: Overexpressing MEF2 in the lateral amygdala blocked long-term memory formation for contextual and cued fear conditioning.
Figure 6: Disrupting MEF2 function permitted robust memory formation after weak training.
Figure 7: Memory disruption produced by increasing MEF2 rescued by disrupting AMPAR endocytosis.


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We thank A. DeCristofaro, R. Braybon and M. Yamamoto for excellent technical assistance. This work was supported by grants from the Canadian Institutes of Health Research (CIHR; MOP-74650 (S.A.J.), MOP-86762 (P.W.F.)), EJLB Foundation (S.A.J.) and Natural Science and Engineering Research Council (S.A.J.). C.J.C., A.P.Y. and M.J.S. were supported by Restracomp Fellowships (Hospital for Sick Children), A.P.Y. received support from the Alzheimer's Society of Canada, M.J.S. received a CIHR Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award and a grant from the Faculty of Medicine at the University of Toronto, and C.J.C. received an Ontario Graduate Scholarship.

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S.A.J. and P.W.F. designed, directed and coordinated the study. C.J.C., V.M., L.R. and T.P. conducted behavioral experiments . C.J.C., A.P.Y. and M.J.S. performed the surgeries. C.J.C., V.M. and L.R. performed spine analysis. V.M., L.R. and G.V. performed immunohistochemistry. V.M. and P.J.R. conducted the cell culture experiments. C.J.C., V.M. and L.R. performed statistical analysis. J.-H.H. designed several constructs. R.L.N. generated viral vectors, shRNA and commented extensively on the design of experiments and use of viral vectors. S.A.J. and P.W.F. wrote the manuscript, with assistance from C.J.C., V.M. and L.R.

Correspondence to Sheena A Josselyn.

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Cole, C., Mercaldo, V., Restivo, L. et al. MEF2 negatively regulates learning-induced structural plasticity and memory formation. Nat Neurosci 15, 1255–1264 (2012).

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