Rates of cerebral protein synthesis are elevated in a Shank3 knockout mouse model

Authors

• A Torossian
• RM Saré
• C Figueroa
• CB Smith

Abstract

SHANK proteins are scaffolding proteins found in the post-synaptic density of excitatory synapses. These proteins work to enhance signal transduction and synaptic development. Mutations in SHANK genes (SHANK1, SHANK2, and SHANK3) lead to dysfunctional synaptic development and are associated with neurodevelopmental disorders such as autism spectrum disorder (ASD). Disruption of SHANK3 is associated with Phelan-McDermid syndrome (PMS), characterized by intellectual disability and autism-like behaviors. Relative to the other SHANK genes, SHANK3 mutations are correlated with more severe intellectual disability and impairments in learning and memory. Since the process of learning and memory is protein synthesis dependent, we hypothesized that deficits in PMS would be reflected in effects on brain protein synthesis. We used a Shank3 knockout (KO) mouse model on a C57BL/6J background and the quantitative autoradiographic L-[1-14C]leucine method to quantify regional rates of cerebral protein synthesis (rCPS) in vivo. We compared rCPS in adult male littermates, Shank3 KO (n=9) with wild-type (WT) (n=8) in 16 brain regions. Results were analyzed by means of a two-way ANOVA with genotype and region as factors. The main effect of genotype was statistically significant (p ≤ 0.02). In most brain regions analyzed, rCPS were higher (16-29%) in Shank3 KO mice. Our results suggest that elevated rCPS may be a biochemical characteristic of PMS. This finding is of interest considering parallel findings of dysregulated brain protein synthesis in other neurodevelopmental disorders such as fragile X syndrome and tuberous sclerosis complex.

Scientific Focus Area: Neuroscience

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