TY  - GEN
TI  - Dissecting hormonal and transient effects in
Shankopathies associated with autism spectrum
disorder
AV  - public
A1  - Eltokhi, Ahmed
N2  - Postsynaptic scaffolding proteins like SHANK1-3 stabilize the formation, organization and signal
transmission at the glutamatergic synapses through numerous protein interactions. All three SHANK
genes are expressed in multiple isoforms that cooperate to form a complex and a developmentaldependent scaffold organization at glutamatergic synapses. Those modulatory proteins are involved
in the spatial organization of postsynaptic receptors, the efficiency of synaptic transmission and the
plasticity of synapses. As a consequence, the synaptic transmission is responsive to structural
changes within the SHANK scaffold, as evidenced by (I) the high number of ASD patients with
mutations and copy number variations in the SHANK genes, (II) the diverse clinical phenotypes
ranging from ASD to mania-like phenotypes in numerous Shank knock-out mouse models and (III)
the 4-fold higher prevalence of ASD in males, which might be explained in some cases by the sex
dimorphic expression of SHANK. Indeed, the here presented investigation of Shank expression in
mice revealed significantly higher SHANK levels both in late stage male embryos and earlypostnatal male pups during their peak of testosterone level. Moreover, the treatment of human
neuroblastoma cells with dihydrotestosterone and 17?-estradiol increased the expression of all three
SHANK genes, demonstrating a direct sensitivity of SHANK genes to the sex hormones.
For the functional analysis of specific SHANK isoforms in mice, the endogenous regulation of the
Shank scaffold was blunted in favor of a strong constitutive, doxycycline-regulated overexpression of
transgenic SHANKs. The spatiotemporal-controlled overexpression of either SHANK2A or the
truncated SHANK2A(R462X) in the mouse glutamatergic forebrain neurons was correlated with
specific ASD-like phenotypes including hyperactivity, repetitive behavior and impairments in social
and novelty behaviors. When the transgenes were switched off in adulthood, specifically the
impaired sociability was unexpectedly rescued in mice of both mouse lines. The effect of SHANK2A
but not SHANK2A(R462X) overexpression inhibited the developmental-dependent AMPAR subtype
switch in the basal dendrites of the hippocampus. In addition, the synaptic protein components were
altered differently in both mouse lines, indicating mainly presynaptic components in
SHANK2A(R462X) and more postsynaptic components in SHANK2A overexpressing mice. These
results identified the differential regulation of endogenous SHANK as critical modulators of neuronal
networks that are critically involved in learning and social behaviors.
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/27223/
CY  - Heidelberg
Y1  - 2020///
ID  - heidok27223
ER  -