Loss of predominant shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission

Mehreen Kouser, Haley E. Speed, Colleen M. Dewey, Jeremy M. Reimers, Allie J. Widman, Natasha Gupta, Shunan Liu, Thomas C. Jaramillo, Muhammad Bangash, Bo Xiao, Paul F. Worley, Craig M. Powell

Research output: Contribution to journalArticle

132 Scopus citations

Abstract

The Shank3 gene encodes a scaffolding protein that anchors multiple elements of the postsynaptic density at the synapse. Previous attempts to delete the Shank3 gene have not resulted in a complete loss of the predominant naturally occurring Shank3 isoforms.Wehave now characterized a homozygous Shank3 mutation in mice that deletes exon 21, including the Homer binding domain. In the homozygous state, deletion of exon 21 results in loss of the major naturally occurring Shank3 protein bands detected by C-terminal and N-terminal antibodies, allowing us to more definitively examine the role of Shank3 in synaptic function and behavior. This loss of Shank3 leads to an increased localization of mGluR5 to both synaptosome and postsynaptic density-enriched fractions in the hippocampus. These mice exhibit a decrease in NMDA/AMPA excitatory postsynaptic current ratio in area CA1 of the hippocampus, reduced long-term potentiation in area CA1, and deficits in hippocampus-dependent spatial learning and memory. In addition, these mice also exhibit motor-coordination deficits, hypersensitivity to heat, novelty avoidance, altered locomotor response to novelty, and minimal social abnormalities. These data suggest that Shank3 isoforms are required for normal synaptic transmission/plasticity in the hippocampus, as well as hippocampus-dependent spatial learning and memory.

Original languageEnglish (US)
Pages (from-to)18448-18468
Number of pages21
JournalJournal of Neuroscience
Volume33
Issue number47
DOIs
StatePublished - Nov 22 2013

ASJC Scopus subject areas

  • Neuroscience(all)

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    Kouser, M., Speed, H. E., Dewey, C. M., Reimers, J. M., Widman, A. J., Gupta, N., Liu, S., Jaramillo, T. C., Bangash, M., Xiao, B., Worley, P. F., & Powell, C. M. (2013). Loss of predominant shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission. Journal of Neuroscience, 33(47), 18448-18468. https://doi.org/10.1523/JNEUROSCI.3017-13.2013