title: Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission.
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. We have 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.
authors.affiliation: Departments of Neurology and Neurotherapeutics and Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8813, and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: Mehreen
authors.initials: M
authors.lastname: Kouser
authors.forename: Haley E
authors.initials: HE
authors.lastname: Speed
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Dewey
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Reimers
authors.forename: Allie J
authors.initials: AJ
authors.lastname: Widman
authors.forename: Natasha
authors.initials: N
authors.lastname: Gupta
authors.forename: Shunan
authors.initials: S
authors.lastname: Liu
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Jaramillo
authors.forename: Muhammad
authors.initials: M
authors.lastname: Bangash
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.forename: Craig M
authors.initials: CM
authors.lastname: Powell
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D001526:Behavioral Symptoms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005106:Exploratory Behavior / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008124:Locomotion / Q000235:genetics; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D057907:Post-Synaptic Density / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011597:Psychomotor Performance / Q000502:physiology; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D013216:Reflex, Startle / Q000235:genetics; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*; D013574:Synaptosomes / Q000378:metabolism / Q000648:ultrastructure
chemical_list: C578936:Grm5 protein, mouse; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D064529:Receptor, Metabotropic Glutamate 5; C492356:Shank3 protein, mouse