Key result
Homozygous disc1 mutation decreases neural pIGF-1Rβ expression in mice while heterozygous mutation increases it.
Why the study?
Although disc1 mutation alters GSK3β and Erk1/2 kinases, it was unclear whether the mutation impacts IGF-1R expression and activity in the brain.
Does disc1 mutation alter neural pIGF-1Rβ and related kinase expression in mice?
Does disc1 mutation alter neural pIGF-1Rβ and related kinase expression in mice?
The disc1 mutation alters pIGF-1Rβ and related kinase expression in a dose-dependent manner in the mouse brain, highlighting potential therapeutic targets for disc1-related neuropsychiatric defects.
Hypothesis-generating for disc1-pIGF-1Rβ signaling in neuropsychiatric models; human translation remains untested.
Mutation of the disc1 gene underlies a broad range of developmental neuropsychiatric defects, including schizophrenia, depression, and bipolar disorder. The pathophysiological phenotypes linked with disc1 mutation are due to the truncation of the DISC1 primary protein structure. This leads to a defective post-synaptic scaffolding and kinase – GSK3 and Erk1/2 – signaling. As a result, synaptic function and maintenance are significantly impaired in the disc1 mutant brain. Among several other pathways, GSK3 and Erk1/2 are involved in insulin-like growth factor 1 receptor (IGF-1R) kinase signaling. Although disc1 mutation alters these kinases, it is unclear if the mutation impacts IGF-1R expression and activity in the brain. Here, we demonstrate that the expression of active IGF-1R (pIGF-1R) is altered in the hippocampus and prefrontal cortex of disc1 mutant mice and vary with the dose of the mutation (homozygous and heterozygous). The expression of pIGF-1Rβ decreased significantly in 129S (hom, disc1-/-) brains. In contrast, the 129S:B6 (het, disc1+/-) brains were characterized by an increase in pIGF-1R when compared with the C57BL/6 (control) level. The decrease in pIGF-1R level for the 129S brains was accompanied by the loss of Akt activity (S473 pAkt) and decreased Ser9 phosphorylation of GSK3 (increased basal GSK3β). Additionally, hippocampal and cortical pErk1/2 activity increased in the 129S hippocampus and cortex. Although 129S:B6 recorded alterations in pIGF-1Rβ-pAkt-GSK3β (like 129S, disc1+/+), there was no observable phenotypic change in pErk1/2 activity for the heterozygote (disc1+/-) mutant. In addition to GSK3β inhibition, we conclude that pIGF-1R, pAkt, and pErk1/2 are potential targets in disc1-/- (hom) mutant brain. On the other hand, pIGF-1R and pAkt can be further explored in disc1+/- (het) brain.
No takes yet. Share an insight, caveat, or question.
Sultana et al. (2020) studied disc1 mutation (model for neuropsychiatric disorders) (n=28). disc1 mutation vs. Wild-type (C57BL/6J) was evaluated on Expression of active IGF-1Rβ (pIGF-1Rβ) in the hippocampus and prefrontal cortex (p=<0.001). Homozygous disc1 mutant mice exhibited a significant decrease in neural pIGF-1Rβ expression, whereas heterozygous mice showed an increase compared to wild-type controls.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: