TY - JOUR
T1 - Loss of predominant shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission
AU - Kouser, Mehreen
AU - Speed, Haley E.
AU - Dewey, Colleen M.
AU - Reimers, Jeremy M.
AU - Widman, Allie J.
AU - Gupta, Natasha
AU - Liu, Shunan
AU - Jaramillo, Thomas C.
AU - Bangash, Muhammad
AU - Xiao, Bo
AU - Worley, Paul F.
AU - Powell, Craig M.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84887841772&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84887841772&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.3017-13.2013
DO - 10.1523/JNEUROSCI.3017-13.2013
M3 - Article
C2 - 24259569
AN - SCOPUS:84887841772
SN - 0270-6474
VL - 33
SP - 18448
EP - 18468
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 47
ER -