AUTHOR=Sultana Razia , Shrestha Amita , Lee Charles C. , Ogundele Olalekan M. 

TITLE=Disc1 Carrier Mice Exhibit Alterations in Neural pIGF-1Rβ and Related Kinase Expression

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=14

YEAR=2020

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2020.00094

DOI=10.3389/fncel.2020.00094

ISSN=1662-5102

ABSTRACT=<p>Mutation of the <italic>disc1</italic> gene underlies a broad range of developmental neuropsychiatric defects, including schizophrenia, depression, and bipolar disorder. The pathophysiological phenotypes linked with <italic>disc1</italic> mutation are due to the truncation of the DISC1 primary protein structure. This leads to a defective post-synaptic scaffolding and kinase—GSK3β and Erk1/2—signaling. As a result, synaptic function and maintenance are significantly impaired in the <italic>disc1</italic> mutant brain. Among several other pathways, GSK3β and Erk1/2 are involved in insulin-like growth factor 1 receptor (IGF-1Rβ) kinase signaling. Although <italic>disc1</italic> 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-1Rβ (pIGF-1Rβ) is altered in the hippocampus and prefrontal cortex (PFC) of <italic>disc1</italic> mutant mice and vary with the dose of the mutation (homozygous and heterozygous). The expression of pIGF-1Rβ decreased significantly in 129S (<italic>hom, disc1</italic><sup>−/−</sup>) brains. In contrast, 129S:B6 (<italic>het, disc1</italic><sup>+/−</sup>) brains were characterized by an increase in pIGF-1Rβ when compared with the C57BL/6 (<italic>disc1</italic><sup>+/+</sup>) level. The decrease in pIGF-1Rβ level for the 129S brains was accompanied by the loss of Akt activity (S473 pAkt) and decreased Ser9 phosphorylation of GSK3β (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), there was no observable change in pErk1/2 activity for the heterozygote (<italic>disc1</italic><sup>+/−</sup>) mutant. In addition to GSK3β inhibition, we conclude that pIGF-1R, pAkt, and pErk1/2 are potential targets in <italic>disc1</italic><sup>−/−</sup> mutant brain. On the other hand, pIGF-1R and pAkt can be further explored in <italic>disc1</italic><sup>+/−</sup> brain.</p>