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Zhang et al. Ageing Neur Dis 2023;3:24 https://dx.doi.org/10.20517/and.2023.18 Page 5 of 13

Table 1. SHANK3 mutant animal models

Modifications Targeted exons and
Species/Background Molecular phenotype Behavioral phenotype Ref.
approach isoforms
Drosophila/mef2-Gal4 KO - Minos transposable - Glutamate receptors and active zones are not affected - No reported [35]
element - A defect in postsynaptic development
D101
(shank homozygotes) - Downregulation of
- Loss of 97% coding region Wnt signaling pathway
of the shank gene - Defective NMJ bouton formation and maturation
1118 8k
Drosophila/W KO - Exons4-12 (shank ) - Developmental defects of synapse in the calyx - Reduced motor ability and defective olfactory acuity [34]
749
- Exon10 (shank ) - Ultrastructural defects of synaptic boutons in the adult calyx
138
- Exon5 (shank ) - Normal NMJ development
- Loss of all known SHANK
protein isoforms
Zebrafish/Tu KO - Exon2 (ANK)/homozygous - Reduced protein expression of NeuN, homer1, and - Reduced alertness or reduced danger awareness [37]
- Loss of shank3b synaptophysin - Impaired social interactions and repetitive and
- Exon9 (SH3, PDZ, stereotyped behaviors
SAM)/homozygous
- Loss of shank3a
Zebrafish/The Gulbenkian KO - Exon2 (ANK, SH3, PDZ, - Downregulation of neuroligin gene expression - Social contagion effects and attention-recognition [39]
Institute of Science SAM)/homozygous - Upregulation of BDNF and NeuroD gene expression deficits
- Loss of shank3a
-/-
Zebrafish/The University of KO - shankabΔN - The absence of SHANK3 puncta is observed in the - Downstream brain regions fail to integrate and [38]
Miami zebrafish core facility (ANK)/homozygous cerebellum and along the ventral neural tracts of the respond to dark transitions in larvae,
-/- -/-
- Loss of shank3a/b brainstem, while PSD-95 synaptic puncta remain unaffected both shank3abΔN and shank3abΔC
-/-
- shank3abΔC (near the
PDZ)/homozygous
- Loss of shank3a/b
Zebrafish/Tu KO - Exon2 (ANK, SH3, - Reduced homer1 and synaptophysin protein levels in the adult - Impaired locomotor activity [36]
PDZ)/homozygous zebrafish brain - Abnormal repetitive movements and impaired social
- Loss of shank3b preference behaviors in the adult zebrafish
Mouse/Bruce4 C57BL/6 KO - Exons4-9 - Reductions in glutamatergic synaptic transmission and - Social interaction and social communication deficits [49]
(ANK)/heterozygous plasticity
- Loss of shank3a and shank3b - A reduced number of GluR1 immunoreactive puncta in the
striatum radiatum
Mouse/C57BL/6J KO - Exons4-9 - Altered dendritic spine morphology - Abnormal social behavior [10]
(ANK)/homozygous - Impaired synaptic plasticity - Aberrant motor behaviors and ultrasonic vocalizations
- Loss of shank3a and shank3b - Impaired activity-dependent - Repetitive behaviors
GluA1 redistribution - Deficient learning and memory
- Intact basal transmission function
Mouse/C57 (Jackson) KO - Exons4-7 - Defects at striatal synapses and cortico-striatal circuits - No lesions or anxiety-like behavior [50]
(ANK)/homozygous
- Loss of shank3a
Mouse/C57 (Jackson) KO - Exons13-16 - Reduced spine density, PSD length and thickness - Anxiety-like behavior and excessive [50]
(PDZ)/homozygous - Self-injurious grooming
- Loss of shank3a and shank3b - Dysfunctional social interaction behavior