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Shank3 Mouse Comparison Table.
The mouse table is a work in progress. We will continue to update the table with new findings, replication data, and new mouse models. We hope, over time,
to find a better platform for sharing mouse findings. In the meanwhile, please contact Geraldine Bliss to suggest changes.
N-terminal ankryin repeats → SH3 domain → PDZ domain (PSD-95) → Proline rich domain → C-terminal SAM domain (homer binding domain)
Buxbaum Lab
Jiang Lab
Feng Lab
Feng Lab
Worley Lab
URL/PMID
http://www.ncbi.nlm.nih.gov/pu
bmed/21167025
http://www.ncbi.nlm.nih.gov/pu
bmed/21558424
http://www.ncbi.nlm.nih.gov/pu
bmed/21423165
http://www.ncbi.nlm.nih.gov/pu
bmed/21423165
http://www.ncbi.nlm.nih.gov/pu
bmed/21565394
Mouse
Shank3e4-9 heterozygous
Shank3e4-9 homozygous
Shank3e4-8 homozygous
Shank3e12-13
Shank3e21 (+/ΔC)
Heterozygous
(Shank3a long-form deletion
only, N-terminal fragment not
tested)
(Shank3a long-form deletion
only, N-terminal fragment not
tested)
(Shank3a long-form deletion
only, N-terminal fragment not
tested)
(Shank3a and Shank3b
deletion only, N-terminal
fragment not tested)
Type
Mutation type
Portion of gene targeted
Conditional deletion
Loss of Function
Ankyrin rich domain/exons 4-9
Homozygous KO
Loss of Function
Ankyrin rich domain/exons 4-9
Homozygous KO
Loss of Function
PDZ domain
Protein product deleted
Shank3a--Ankyrin repeat
domains
Shank3a (ankyrin domain)
Homozygous KO
Loss of Function
Ankyrin rich domain/ (exons 48)?
Ankyrin repeats (SHANK3α)
Strain/ Background
C57BL/6
C57BL/6J
Hybrid genetic background
Hybrid genetic background
b-/-
SHANK3α, SHANK3β & portion
of SHANK3γ
Biochemical pathways
perturbed
Mouse phenotype

Seizures

Olfactory

Self-grooming

Repetitive behavior

Rotarod

Anxiety
(Shank3a, Shank3b, Shank3c
all reduced by >80%; Nterminal fragment produced)
Heterozygous Knock-in
Gain-of-function
Homer binding domain/exon
21
Shank3a, Shank3b &
Shank3g--Homer binding site
in Proline rich domain and
SAM domain
Mixed 129s6; C57BL6/J
Increase polyubiquitination of
Shank3 and NR1 due to
reduced crosslinking of Homer
and Shank3.
None observed
No difference from WT
Occasional, with handling
No difference from WT
More self-grooming than WT
(stereotyped, repetitive
behaviors)
No difference from WT
No skin lesions
More self-grooming than WT,
causing skin lesions


Increased head pokes
Novel object exploration
tended to occur from
within the nest, in WT
from outside the nest

Novel objects were
touched only on certain
locations of the object;
WT were not repetitive.
Latency to fall was reduced in
males
No difference in light-dark box
or zero maze
Not explored
No difference from WT
No difference in motor skills

No difference from WT in the
open field, plus maze and
light-dark apparatus

Decreased rearing in
open field test
Decreased time


Social Interaction


Reduced social sniffing
by males in male-female
interactions
No difference in 3
chamber social approach
task





Ultrasonic
vocalizations
Reduced ultrasonic
vocalizations in males in malefemale reciprocal social
interaction context




Motor behavior




Learning & Memory


Less interested in novel
mice than WT
Females more socially
interested than males
Increased non-social,
self focused behaviors
(grooming, sifting
bedding materials)
Decreased social
interactions


Normal initiation of social
interaction
Perturbed recognition of
social novelty




exploring open areas
Increase latency to go to
lit areas
Preferred empty cage to
social partner
Decreased reciprocal
interactions
Decreased frequency of
nose-to-nose interaction
Decreased anogenital
sniffing
Males made more calls
than WT(echolalia?),
females made fewer calls
than WT
WT had more complex
patterns of calls
(monotone speech?)
Reduced duration of calls
compared to WT
More foot faults and
slower movements than
WT, with mutant males
more affected
Decreased locomotion in
open field
No difference in
movement, rearing
activitiy, stereotypical
activities
Morris water maze:
Slower learning time,
increased swim distance,
and circular search
pattern, difficulty in
reversal training
(suggests rigidity of
behavior)
Novel object recognition:
Decreased preference
for novel objects, no
change in duration of
object contacts, controls
made fewer contacts in
LTM and RM tests

Less social investigation
in mice with aggressive
behaviors; mice with
normal aggression were
not different from
controls in social
investigation (aggression
is thought to be a
reaction to change in
social routine)

Preserved social
recognition (more
aggressive with new
mice, less so with
familiar mice)

Longer approach latency
of male to female than
WT
Reduced U/S vocalizations
No change
Morris water maze: no
difference



Morris water maze: no
difference in long term
memory
No difference on short
term spatial recognition
and memory
No difference in fear
memory and extinction





Schizophreniarelated behaviors
Social transmission of
food preference:
Preference for
demonstrator diet was
lost during LTM and RM
tests

Prepulse inhibition: no
difference

Electrophysiology

Striatal
Minimal disruption at corticostriatal synapses




Cortical

Hippocampal
Reduced field population
spikes in striatum
Pre-synaptic function
was not altered,
therefore due to postsynaptic impairment or a
reduction of # of
functional synapses
Reduced AMPARmEPSC frequency and
peak mEPSC amplitude
Reduced NMDAR responses
(due to reduced expression
rather than spine
dysmorphogenesis or deficits
of synapse formation). No
Change in AMPAR mini
frequency or amplitude OR
presynaptic function.






Altered PSD Composition

Down-regulation
Prepulse inhibition, lower
amplitudes and longer
latencies of startle
response than WT
When dosed with
dizocilpine (a
noncompetitive NMDAR
antagonist), levels of
motor activity were much
higher


Reduced basal
glutamatergic synaptic
transmission, reflecting
reduced AMPARmediated transmission
Reduced LTP
No change in LTD
Reduced GluR1 reactivity
Increase in mEPSC
frequency
Decrease in paired-pulse
ratio
AMPA receptors
GluR1





Reduced post-tetanic
potentiation
Reduced LTP
No apparent change in
basal synaptic
transmission
No change in pairedpulse ratio
Impaired activitydependent trafficking of
GluA1 subunits
In PSD-I Fractions

GKAP

Homer1

AMPAR subunit GluA1


No change in field
recordings of population
spikes or PPR from
hippocampal CA1
subregion
Therefore, observed
behavior and synaptic
deficits are specific to
discrete brain regions
and not overall CNS
function
In Striatum

SAPAP3

Homer-1b/c

PSD-93 (Homer1 &




Reduced NMDAR
responses
Reduced NMDAR
dependent LTP and LTD
Reduced LTP induction,
faster LTP decay
mGluR LTD is increased,
and is completely
inhibited by the protein
synthesis inhibitor,
cylcoheximide
In Cortical lysates

NR1 subunit of NMDAR,
w/o reduction of AMPA
(GluR1 or mGluR5)

No change
Morphological defects of
spiny neurons & PSD
morphology

Impaired spine expansion
after LTP (transient rather
than stable)

NMDA subunit NR2A


AMPAR GluA2
NMDAR subunit NR2B


Longer dendritic spines
Decreased spine density
in hippocampus in 4
week old pups












Brain hypertrophy

No obvious alterations in
gross brain structure




Neuronal hypertrophy as
measured by increase in
complexity of:

Dendritic
arborizations

Total dendritic
length

Surface area
increase in medium
spiny neurons
(MSN)
Reduced spine density
No change in spine
length
No change in head
diameter
Larger neck width of
MSN spines
Reduction in mean
thickness of PSD
Reduced PSD length
No change in overall
brain size
Slightly increased
caudate volume








Compounds that enhance
SHANK1
SHANK2
GKAP
AMPA type glutamate
receptors
PSD-95
Homer
Neuroligin
mGlur5
NR2A
NR2B
No change in:

Synaptic
morphology

Syanpse number
Using cortex EM images,
no change in:

PSD length

PSD thickness

Spine density

Spine volume
No Change in cortical layers

Polyubiquitinization
Possible therapeutic direction
No difference in brain
weight
Normal brain anatomy
DLG2)
Glutamate receptor
subunits:

GluR2/GRIA2

NR2A/GRIN2A

NR2B/GIN2B
Increased
polyubiquitinization of
Shank3 = increased
proteasomal degradation

Reduced WT Shank3
70%

90% reduction in
synaptic shank3

90% in synaptic fractions

70% reduction of
synaptic NR1
mGluR antagonists
glutamatergic transmission,
specifically AMPAkines
NMDAR partial co-agonists or
Glycine Transport inhibition
Ubiquitin ligase inhibitors