Abstract
Multiple activity-dependent programs of gene expression orchestrate the development and function of neural circuitries. The local synthesis of proteins in neuronal dendrites is critical for enduring forms of synaptic plasticity that might be a cellular substrate for information storage. Here, I will summarize our recent findings that implicate microRNAs (miRNAs) in the control of dendritic protein synthesis and synaptic plasticity in mammalian neurons. Large-scale functional screening indicates that at least three different miRNAs are involved in the morphological plasticity of dendritic spines, the specialized dendritic structures of synaptic contact. Detailed mechanistic studies revealed that miRNA-mediated regulation of dendritic proteins synthesis impinges on critical modulators of the actin cytoskeleton within spines. Dendritic miRNAs are subject to activity-dependent regulation at both the transcriptional and post-transcriptional levels, implicating miRNAs in the experience-dependent remodeling of neural circuits. By coordinating the global and local fine-tuning of proteins synthesis in response to activity, miRNAs might play a pivotal role in the maintenance of cellular and network homeostasis. Aberrant miRNA expression and/or function could underlie neuropsychiatric disorders that are characterized by defective homeostasis.
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References
Ashraf SI, McLoon AL, Sclarsic SM, Kunes S (2006) Synaptic protein synthesis associated with memory is regulated by the RISC pathway in Drosophila. Cell 124:191–205
Bonhoeffer T, Yuste R (2002) Spine motility. Phenomenology, mechanisms, and function. Neuron 35:1019–1027
Eberwine J, Miyashiro K, Kacharmina JE, Job C (2001) Local translation of classes of mRNAs that are targeted to neuronal dendrites. Proc Natl Acad Sci USA 98:7080–7085
Fiore R, Siegel G, Schratt G (2008) MicroRNA function in neuronal development, plasticity and disease. Biochim Biophys Acta 1779:471–478
Fiore R, Khudayberdiev S, Christensen M, Siegel G, Flavell SW, Kim TK, Greenberg ME, Schratt G (2009) Mef2-mediated transcription of the miR379-410 cluster regulates activity-dependent dendritogenesis by fine-tuning Pumilio2 protein levels. Embo J 28:697–710
Flavell SW, Greenberg ME (2008) Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu Rev Neurosci 31:563–590
Flavell SW, Cowan CW, Kim TK, Greer PL, Lin Y, Paradis S, Griffith EC, Hu LS, Chen C, Greenberg ME (2006) Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 311:1008–1012
Hering H, Sheng M (2001) Dendritic spines: structure, dynamics and regulation. Nature Rev Neurosci 2:880–888
Hong EJ, West AE, Greenberg ME (2005) Transcriptional control of cognitive development. Curr Opin Neurobiol 15:21–28
Kang R, Wan J, Arstikaitis P, Takahashi H, Huang K, Bailey AO, Thompson JX, Roth AF, Drisdel RC, Mastro R, Green WN, Yates JR, 3rd, Davis NG, El-Husseini A (2008) Neural palmitoyl-proteomics reveals dynamic synaptic palmitoylation. Nature 456:904–909
Kiebler MA, DesGroseillers L (2000) Molecular insights into mRNA transport and local translation in the mammalian nervous system. Neuron 25:19–28
Kloosterman WP, Plasterk RH (2006) The diverse functions of microRNAs in animal development and disease. Dev Cell 11:441–450
Kosik KS (2006) The neuronal microRNA system. Nature Rev Neurosci 7:911–920
Kurose H (2003) Galpha12 and Galpha13 as key regulatory mediator in signal transduction. Life Sci 74:155–161
Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T (2002) Identification of tissue-specific microRNAs from mouse. Curr Biol 12:735–739
Lugli G, Larson J, Martone ME, Jones Y, Smalheiser NR (2005) Dicer and eIF2c are enriched at postsynaptic densities in adult mouse brain and are modified by neuronal activity in a calpain-dependent manner. J Neurochem 94:896–905
Obernosterer G, Leuschner PJ, Alenius M, Martinez J (2006) Post-transcriptional regulation of microRNA expression. RNA 12:1161–1167
Peng YR, He S, Marie H, Zeng SY, Ma J, Tan ZJ, Lee SY, Malenka RC, Yu X (2009) Coordinated changes in dendritic arborization and synaptic strength during neural circuit development. Neuron 61:71–84
Ramocki MB, Zoghbi HY (2008) Failure of neuronal homeostasis results in common neuropsychiatric phenotypes. Nature 455:912–918
Sajikumar S, Navakkode S, Frey JU (2005) Protein synthesis-dependent long-term functional plasticity: methods and techniques. Curr Opin Neurobiol 15:607–613
Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439:283–289
Shalizi A, Gaudilliere B, Yuan Z, Stegmuller J, Shirogane T, Ge Q, Tan Y, Schulman B, Harper JW, Bonni A (2006) A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation. Science 311:1012–1017
Siegel G, Obernosterer G, Fiore R, Oehmen M, Bicker S, Christensen M, Khudayberdiev S, Leuschner PJ, Busch CL, Kane CG, Hübel K, Dekker F, Rengarajan B, Drepper C, Waldmann H, Kauppinen S, Greenberg ME, Draguhn A, Rehmsmeier M, Martinez J, Schratt G (2009) A functional screen implicates microRNA-138-dependent regulation of the depalmitoylation enzyme APT1 in dendritic spine morphogenesis. Nature Cell Biol 11:705–716
Steward O, Schuman EM (2001) Protein synthesis at synaptic sites on dendrites. Annu Rev Neurosci 24:299–325
Turrigiano G (2007) Homeostatic signaling: the positive side of negative feedback. Curr Opin Neurobiol 17:318–324
Waites CL, Craig AM, Garner CC (2005) Mechanisms of vertebrate synaptogenesis. Annu Rev Neurosci 28:251–274
Wayman GA, Davare M, Ando H, Fortin D, Varlamova O, Cheng HY, Marks D, Obrietan K, Soderling TR, Goodman RH, Impey S (2008) An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP. Proc Natl Acad Sci USA 105:9093–9098
Zeng Y, Sankala H, Zhang X, Graves PR (2008) Phosphorylation of Argonaute 2 at serine-387 facilitates its localization to processing bodies. Biochem J 413:429-436
Acknowledgments
I thank G. Siegel for help with the illustrations, R. Fiore for critically reading the manuscript and all members of my laboratory for stimulating discussions. Work in my laboratory is funded by the Deutsche Forschungsgemeinschaft (DFG, SFB488), the Human Frontier Science Program (HFSP, CDA) and the National Institute on Drug Abuse (NIDA, 1R21DA025102-01).
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Schratt, G.M. (2010). Fine-tuning mRNA Translation at Synapses with microRNAs. In: De Strooper, B., Christen, Y. (eds) Macro Roles for MicroRNAs in the Life and Death of Neurons. Research and Perspectives in Neurosciences. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-04298-0_5
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DOI: https://doi.org/10.1007/978-3-642-04298-0_5
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