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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