Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology

Abstract

Mutations in the postsynaptic scaffolding gene SHANK2 have recently been identified in individuals with autism spectrum disorder (ASD) and intellectual disability. However, the cellular and physiological consequences of these mutations in neurons remain unknown. We have analyzed the functional impact caused by two inherited and one de novo SHANK2 mutations from ASD individuals (L1008_P1009dup, T1127M, R462X). Although all three variants affect spine volume and have smaller SHANK2 cluster sizes, T1127M additionally fails to rescue spine volume in Shank2 knock-down neurons. R462X is not able to rescue spine volume and dendritic branching and lacks postsynaptic clustering, indicating the most severe dysfunction. To demonstrate that R462X when expressed in mouse can be linked to physiological effects, we analyzed synaptic transmission and behavior. Principal neurons of mice expressing rAAV-transduced SHANK2-R462X present a specific, long-lasting reduction in miniature postsynaptic AMPA receptor currents. This dominant negative effect translates into dose-dependent altered cognitive behavior of SHANK2-R462X-expressing mice, with an impact on the penetrance of ASD.

Molecular basis of dendritic atrophy and activity in stress susceptibility

“…EGR3 displayed increased binding to the promoter of RhoA , a gene involved in negative regulation of dendritic structure 37 and to Actn1 , an actin-associated gene (Figure 4b). Furthermore, EGR3 binding to the Shank2 promoter, a gene involved in regulating dendritic morphology and cognitive behavior, 38 was decreased.…”

Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers

“…Human genetic studies have implicated SHANK2 in ASDs (5), and previous rodent experiments have reported autism-like behaviors in two different lines of Shank2 mutant mice (26,27). We conducted a series of behavioral tests to assess whether Δe24 -/-mice would display ASD-like and intellectual disability-like phenotypes similar to those associated with SHANK2 mutations in humans (4,5,39). We tested social behaviors using a sociability paradigm, which revealed no significant deficiencies in the Δe24 -/-mice of either sex ( Figure 3A and Supplemental Figure 3C).…”

Role of the nitric oxide donor sodium nitroprusside in the antidepressant effect of ketamine in mice

“…For each sample, the system recorded position, object area and the status of defined events. Parameters assessed were total distance moved, velocity, and time in center, which was defined as the area 10 cm distant from the walls, as earlier described (Fuss et al, 2010;Berkel et al, 2012).…”