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The Journal of Neuroscience, June 13, 2007, 27(24):6400-6411; doi:10.1523/JNEUROSCI.5211-06.2007

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Cellular/Molecular
Cytoplasmic Polyadenylation Element Binding Protein 1-Mediated mRNA Translation in Purkinje Neurons Is Required for Cerebellar Long-Term Depression and Motor Coordination

Michael McEvoy, ^* Guan Cao, ^* Paula Montero Llopis, Mitchell Kundel, Kendrick Jones, Catherine Hofler, Chan Shin, and David G. Wells

Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06520

Correspondence should be addressed to David G. Wells, 219 Prospect Street, KBT 226, Box 208103, Yale University, New Haven, CT 06520-8103. Email: david.wells{at}yale.edu

The ability of neurons to modify synaptic connections is critical for proper brain development and function in the adult. It is now clear that changes in synaptic strength are often accompanied by changes in synaptic morphology. This synaptic plasticity can be maintained for varying lengths of time depending on the type of neuronal activity that first induced the changes. Long-term synaptic plasticity requires the synthesis of new proteins, and one mechanism for the regulation of experience-induced protein synthesis in neurons involves cytoplasmic polyadenylation element binding protein (CPEB1). CPEB1 can bidirectionally regulate mRNA translation, first repressing translation, and then activating translation after the phosphorylation of two critical residues (T¹⁷¹ and S¹⁷⁷). To determine the full extent of CPEB1-mediated protein synthesis in synaptic function, we engineered a line of mice expressing CPEB1 with these phosphorylation sites mutated to alanines (mCPEB1-AA) exclusively in cerebellar Purkinje neurons (PNs). Thus, mRNAs bound by mCPEB1-AA would be held in a translationally dormant state. We show that mCPEB1-AA localizes to synapses in cerebellum and resulted in a loss of protein synthesis-dependent phase of parallel fiber–PN long-term depression. This was accompanied by a change in spine number and spine length that are likely attributable in part to the dysregulation of IRSp53, a protein known to play a role in synaptic structure. Finally, mCPEB1-AA mice displayed a significant impairment of motor coordination and a motor learning delay.

Key words: mRNA translation; synaptic plasticity; Aurora kinase; LTD; dendritic spine; cerebellum

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Received Dec. 1, 2006; revised May 3, 2007; accepted May 4, 2007.

Correspondence should be addressed to David G. Wells, 219 Prospect Street, KBT 226, Box 208103, Yale University, New Haven, CT 06520-8103. Email: david.wells{at}yale.edu

This article has been cited by other articles:

				M. Kundel, K. J. Jones, C. Y. Shin, and D. G. Wells Cytoplasmic Polyadenylation Element-Binding Protein Regulates Neurotrophin-3-Dependent {beta}-Catenin mRNA Translation in Developing Hippocampal Neurons J. Neurosci., October 28, 2009; 29(43): 13630 - 13639. [Abstract] [Full Text] [PDF]

				J. E. Bestman and H. T. Cline The RNA binding protein CPEB regulates dendrite morphogenesis and neuronal circuit assembly in vivo PNAS, December 23, 2008; 105(51): 20494 - 20499. [Abstract] [Full Text] [PDF]

				G. Cao and C.-P. Ko Schwann Cell-Derived Factors Modulate Synaptic Activities at Developing Neuromuscular Synapses J. Neurosci., June 20, 2007; 27(25): 6712 - 6722. [Abstract] [Full Text] [PDF]

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