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The Journal of Neuroscience, February 13, 2008, 28(7):1697-1708; doi:10.1523/JNEUROSCI.3032-07.2008

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Development/Plasticity/Repair
Smaller Dendritic Spines, Weaker Synaptic Transmission, but Enhanced Spatial Learning in Mice Lacking Shank1

Albert Y. Hung,^1,2 Kensuke Futai,¹ Carlo Sala,³ Juli G. Valtschanoff,⁴ Jubin Ryu,¹ Mollie A. Woodworth,¹ Fleur L. Kidd,¹ Clifford C. Sung,¹ Tsuyoshi Miyakawa,⁵ Mark F. Bear,¹ Richard J. Weinberg,⁴ and Morgan Sheng¹

¹The Picower Institute for Learning and Memory, The Institute of Physical and Chemical Research (RIKEN)-Massachusetts Institute of Technology Neuroscience Research Center, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, ²Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02114, ³Consiglio Nazionale delle Ricerche, Institute of Neuroscience, Cellular and Molecular Pharmacology, Department of Pharmacology, University of Milan, 20129 Milan, Italy, ⁴Department of Cell and Developmental Biology, and Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, and ⁵Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan

Correspondence should be addressed to Morgan Sheng, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 46-4303, Cambridge, MA 02139. Email: msheng{at}mit.edu

Experience-dependent changes in the structure of dendritic spines may contribute to learning and memory. Encoded by three genes, the Shank family of postsynaptic scaffold proteins are abundant and enriched in the postsynaptic density (PSD) of central excitatory synapses. When expressed in cultured hippocampal neurons, Shank promotes the maturation and enlargement of dendritic spines. Recently, Shank3 has been genetically implicated in human autism, suggesting an important role for Shank proteins in normal cognitive development. Here, we report the phenotype of Shank1 knock-out mice. Shank1 mutants showed altered PSD protein composition; reduced size of dendritic spines; smaller, thinner PSDs; and weaker basal synaptic transmission. Standard measures of synaptic plasticity were normal. Behaviorally, they had increased anxiety-related behavior and impaired contextual fear memory. Remarkably, Shank1-deficient mice displayed enhanced performance in a spatial learning task; however, their long-term memory retention in this task was impaired. These results affirm the importance of Shank1 for synapse structure and function in vivo, and they highlight a differential role for Shank1 in specific cognitive processes, a feature that may be relevant to human autism spectrum disorders.

Key words: postsynaptic density; gene knock-out; learning and memory; dendritic spine; autism; scaffolding proteins

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Received July 4, 2007; revised Nov. 20, 2007; accepted Dec. 15, 2007.

Correspondence should be addressed to Morgan Sheng, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 46-4303, Cambridge, MA 02139. Email: msheng{at}mit.edu

This article has been cited by other articles:

				J. Ryu, K. Futai, M. Feliu, R. Weinberg, and M. Sheng Constitutively Active Rap2 Transgenic Mice Display Fewer Dendritic Spines, Reduced Extracellular Signal-Regulated Kinase Signaling, Enhanced Long-Term Depression, and Impaired Spatial Learning and Fear Extinction J. Neurosci., August 13, 2008; 28(33): 8178 - 8188. [Abstract] [Full Text] [PDF]

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