GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:21558424

From GONUTS
Jump to: navigation, search
Citation

Wang, X, McCoy, PA, Rodriguiz, RM, Pan, Y, Je, HS, Roberts, AC, Kim, CJ, Berrios, J, Colvin, JS, Bousquet-Moore, D, Lorenzo, I, Wu, G, Weinberg, RJ, Ehlers, MD, Philpot, BD, Beaudet, AL, Wetsel, WC and Jiang, YH (2011) Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum. Mol. Genet. 20:3093-108

Abstract

SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density (PSD) of excitatory synapses. Small microdeletions and point mutations in SHANK3 have been identified in a small subgroup of individuals with autism spectrum disorder (ASD) and intellectual disability. SHANK3 also plays a key role in the chromosome 22q13.3 microdeletion syndrome (Phelan-McDermid syndrome), which includes ASD and cognitive dysfunction as major clinical features. To evaluate the role of Shank3 in vivo, we disrupted major isoforms of the gene in mice by deleting exons 4-9. Isoform-specific Shank3(e4-9) homozygous mutant mice display abnormal social behaviors, communication patterns, repetitive behaviors and learning and memory. Shank3(e4-9) male mice display more severe impairments than females in motor coordination. Shank3(e4-9) mice have reduced levels of Homer1b/c, GKAP and GluA1 at the PSD, and show attenuated activity-dependent redistribution of GluA1-containing AMPA receptors. Subtle morphological alterations in dendritic spines are also observed. Although synaptic transmission is normal in CA1 hippocampus, long-term potentiation is deficient in Shank3(e4-9) mice. We conclude that loss of major Shank3 species produces biochemical, cellular and morphological changes, leading to behavioral abnormalities in mice that bear similarities to human ASD patients with SHANK3 mutations.

Links

PubMed PMC3131048 Online version:10.1093/hmg/ddr212

Keywords

Animals; Behavior, Animal/physiology; Carrier Proteins/genetics; Carrier Proteins/metabolism; Female; Learning/physiology; Male; Memory/physiology; Mice; Motor Activity/genetics; Motor Activity/physiology; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Protein Isoforms/genetics; Protein Isoforms/metabolism; RNA, Messenger/genetics; Synapses/metabolism; Synapses/physiology; Synaptic Transmission/genetics; Synaptic Transmission/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:GRIA1

located_in

GO:0043005: neuron projection

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GRIA2

located_in

GO:0043005: neuron projection

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NMDE1

located_in

GO:0043005: neuron projection

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:DLGP1

located_in

GO:0014069: postsynaptic density

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HOME1

located_in

GO:0014069: postsynaptic density

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NMDE1

GO:0043005: neuron projection

ECO:0000315:

C

Figure 6B and D, A decrease of receptor subunit in synaptosome membrane fraction. There was a decrease in NR2A subunit in mutant shank3 mice compared to control .

complete
CACAO 3126

MOUSE:NMDE1

part_of

GO:0043005: neuron projection

ECO:0000315: mutant phenotype evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NMDE1

part_of

GO:0043005: neuron projection

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HOME1

part_of

GO:0014069: postsynaptic density

ECO:0000315: mutant phenotype evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HOME1

part_of

GO:0014069: postsynaptic density

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HOME1

GO:0014069: postsynaptic density

ECO:0000315:

C

Figure 6A and C, A decrease of PSD proteins in postsynaptic density fraction. There was a decrease in homer 1 protein in mutant Shank3 mice. Similar results was seen in figure 6E, confirmed by quantitative analyses.

complete
CACAO 3129

MOUSE:GRIA1

part_of

GO:0043005: neuron projection

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:GRIA1

GO:0019717: synaptosome

ECO:0000315:

C

Figure 6B and D, A decrease of receptor subunit in synaptosome membrane fraction. There was a decrease in GluA1 subunit in mutant Shank3 mice compared to control. Similar results was seen in figure 6E, confirmed by quantitative analyses.

complete
CACAO 3128

MOUSE:SHAN3

acts_upstream_of_or_within

GO:0007611: learning or memory

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5056336

P

Seeded From UniProt

complete

MOUSE:SHAN3

acts_upstream_of_or_within

GO:0007626: locomotory behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5056336

P

Seeded From UniProt

complete

MOUSE:SHAN3

involved_in

GO:0035641: locomotory exploration behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHAN3

involved_in

GO:0060291: long-term synaptic potentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHAN3

involved_in

GO:0097113: AMPA glutamate receptor clustering

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHAN3

involved_in

GO:0097114: NMDA glutamate receptor clustering

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHAN3

involved_in

GO:0097117: guanylate kinase-associated protein clustering

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHAN3

involved_in

GO:1900271: regulation of long-term synaptic potentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHAN3

involved_in

GO:0035640: exploration behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHAN3

involved_in

GO:2000821: regulation of grooming behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHAN3

GO:0035176: social behavior

ECO:0000315:

P

Control mice showed more affiliation with novel social stimulus than mutant Shank3 mice, figure 2A and B. Also when mice given choice of interacting with social or non-social stimulus, mutant Shank3 mice failed to show social affiliation compared to control. Similar results seen in figure 2C, mutant mice did not initiate the first social interaction.

complete
CACAO 3113

MOUSE:SHAN3

GO:0071625: vocalization behavior

ECO:0000315:

P

Ultrasonic vocalization investigated. Control Shank3 mice showed more vocal (figure 2G) and complex calls than mutant mice (figure 2H). Control mice showed more long duration calls than mutant Shank3 mice but the opposite was seen in mutant Shank3 where more short duration calls were made compared to wild type (figure 2I and J)

complete
CACAO 3114

MOUSE:SHAN3

GO:0050885: neuromuscular process controlling balance

ECO:0000315:

P

To test motor coordination, foot misplacement test was done where there is a arena comprised of 16 parallel stainless-steel rods spaced 6 mm apart. A touch-sensor is used to record when the mouse foot slipped (losing balance) between the bars and was recorded as a foot-fault. Figure 3A showed mutant mice had more foot faults than control.

complete
CACAO 3115

MOUSE:SHAN3

GO:0040011: locomotion

ECO:0000315:

P

Locomotion was decreased in mutant Shank3 mice compared to control (figure 3C)

complete
CACAO 3116

MOUSE:SHAN3

GO:0007612: learning

ECO:0000315:

P

Figure 3D and E showed that control increase in latency to fall off an accelerating rotorod compared to mutant male Shank3 mice where the latency did not change indicating no learning was taking place.

complete
CACAO 3117

MOUSE:SHAN3

GO:2000821: regulation of grooming behavior

ECO:0000315:

P

Shank3 mutant mice showed more self grooming behaviour compared to control, figure 3H

complete
CACAO 3118

MOUSE:SHAN3

GO:0035640: exploration behavior

ECO:0000315:

P

Novel object exploration was investigated from inside and outside the nest. Shank3 control mice made contact with novel object more often from outside than inside the nest whereas mutant Shank3 mice made contact with novel object more from inside the nest than outside the nest. Indicating less exploration behaviour in mutant mice compared to control. Similar results seen in figure 3G mutant mice made same location of contact against novel object where as control mice made contact as different locations of the novel object.

complete
CACAO 3119

MOUSE:SHAN3

GO:0007613: memory

ECO:0000315:

P

Morse water maze, mutant Shank3 mice showed more circular search swim patterns to the platform than control mice (supplementary material figure S4F top right). Also figure 4A right, when platform was changed, swim distance was the same for both control and mutant on day 7 but swim distance decreased after that for control but not for mutants. Figure 4A left showed that decline in swim distance over the first 3 day was less rapid in mutant Shank3 mice compared to control. Similar result seen in figure 4D, E G, H.

complete
CACAO 3120

MOUSE:SHAN3

GO:0060997: dendritic spine morphogenesis

ECO:0000315:

P

Figure 5C shows mutant Shank3 mice had longer dendritic spine compared to control. Figure 5I and J showed spine density was reduced and length was increased in CA1 hippocampus in four week old mice. Similar result seen in week 10 mice (figure 5K and L)

complete
CACAO 3121

MOUSE:SHAN3

GO:0097117: guanylate kinase-associated protein clustering

ECO:0000315:

P

Figure 6A and C, A decrease of PSD proteins in postsynaptic density fraction. There was a decrease in GKAP protein.

complete
CACAO 3122

MOUSE:SHAN3

GO:0097113: alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor clustering

ECO:0000315:

P

Figure 6B and D, A decrease of receptor subunit in synaptosome membrane fraction. There was a decrease in GluA1 subunit in mutant Shank3 mice compared to control. Similar results was seen in figure 6E, confirmed by quantitative analyses.

complete
CACAO 3123

MOUSE:SHAN3

GO:0097114: N-methyl-D-aspartate receptor clustering

ECO:0000315:

P

Figure 6B and D, A decrease of receptor subunit in synaptosome membrane fraction. There was a decrease in NR2A subunit in mutant Shank3 mice compared to control.

complete
CACAO 3124

MOUSE:SHAN3

GO:0060291: long-term synaptic potentiation

ECO:0000315:

P

Figure 7A, mutant Shank3 mice showed reduced hippocampal long term potentiation compared to control.

complete
CACAO 3125

MOUSE:SHAN3

acts_upstream_of_or_within

GO:0035176: social behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5056336

P

Seeded From UniProt

complete

MOUSE:SHAN3

involved_in

GO:0060997: dendritic spine morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHAN3

involved_in

GO:0007613: memory

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHAN3

involved_in

GO:0071625: vocalization behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHAN3

involved_in

GO:0050885: neuromuscular process controlling balance

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHAN3

involved_in

GO:0007612: learning

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHAN3

involved_in

GO:0040011: locomotion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHAN3

involved_in

GO:0035176: social behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:SHAN3

acts_upstream_of_or_within

GO:1904717: regulation of AMPA glutamate receptor clustering

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5056336

P

Seeded From UniProt

complete

MOUSE:SHAN3

acts_upstream_of_or_within

GO:0071625: vocalization behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5056336

P

Seeded From UniProt

complete

MOUSE:SHAN3

acts_upstream_of_or_within

GO:0060997: dendritic spine morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5056336

P

Seeded From UniProt

complete

MOUSE:SHAN3

acts_upstream_of_or_within

GO:0048167: regulation of synaptic plasticity

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5056336

P

Seeded From UniProt

complete

MOUSE:DLGP1

GO:0014069: postsynaptic density

ECO:0000315:

C

Figure 6A and C, A decrease of PSD proteins in postsynaptic density fraction. There was a decrease in GKAP protein in mutant Shank3 mice.

complete
CACAO 3131

MOUSE:DLGP1

part_of

GO:0014069: postsynaptic density

ECO:0000315: mutant phenotype evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:DLGP1

part_of

GO:0014069: postsynaptic density

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

See Help:References for how to manage references in GONUTS.