Objectives: To evaluate the role of SHANK3 in the development of motor and other behavioral deficits associated with autism in Shank3 mutant mice.
Methods: We generated Shank3 isoform specific (exons 4-9 deletion, e4-9) and complete knockout (exons 4-22 deletion, e4-22) mutant mice using a conventional and Cre-loxP gene-targeting approach. All Shank3 mice used in the experiments had been backcrossed for more than seven generations onto a C57BL/6J background. Mice were assessed for biochemical, morphological, electrophysiological, and behavioral abnormalities. Motor assessment included the following: 1) a test of in which animals attempted to balance on an accelerating rotorod, 2) a test of balance in which they walked along narrow bars and “foot-faults” were counted, and 3) measurement of stride length and width and fore and rear foot-placement rotation-angle during movement.
Results: Isoform-specific Shank3e4-9 homozygous mutant mice displayed abnormal social behaviors, altered communication patterns, repetitive behaviors and impairments in learning and memory. Mutant mice also demonstrated deficiencies in gait and foot-misplacement tests in both sexes, but Shank3e4-9 -/- male mice showed more severe impairments than females in motor coordination as assessed with a rotorod test. Shank3e4–9 mice had reduced levels of Homer1b/c, GKAP and GluA1 at the PSD, and showed attenuated activity-dependent redistribution of GluA1-containing AMPA receptors. Subtle morphological alterations in dendritic spines were also observed. Analysis of Shank3e4-22 mice is ongoing and data will be presented.
Conclusions: 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 patients with autism and SHANK3 mutations. Prominent among these behavioral abnormalities were significant motor impairments that disproportionately affect male mutant mice suggesting compromised development of functional brain systems underlying motor development in SHANK3 deficiency associated autism.
See more of: Cell Biology
See more of: Biological Mechanisms