AUTHOR=Liu Jia-Ren , Han Xiao Hui , Yuki Koichi , Soriano Sulpicio G. TITLE=Ketamine modulates disrupted in schizophrenia-1/glycogen synthase kinase-3β interaction JOURNAL=Frontiers in Molecular Neuroscience VOLUME=Volume 17 - 2024 YEAR=2024 URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2024.1342233 DOI=10.3389/fnmol.2024.1342233 ISSN=1662-5099 ABSTRACT=Introduction: Disrupted in schizophrenia-1 (DISC1) is a scaffolding protein whose mutated form has been linked to schizophrenia, bipolar affective disorders, and recurrent major depression. DISC1 regulates multiple signaling pathways involved in neurite outgrowth and cortical development and binds directly to glycogen synthase kinase-3β (GSK-3β). Since ketamine activates GSK-3β, we examined the impact of ketamine on DISC1 and GSK-3β expression.Methods: Postnatal day 7 rat pups were treated with ketamine with and without the nonspecific GSK-3β antagonist, lithium. Cleaved caspase-3, GSK-3β and DISC1 levels were measured by immunoblots and DISC1 co-localization in neurons by immunofluorescence. Binding of DISC1 to GSK-3β was determined by co-immunoprecipitation. Neurite outgrowth was determined by measuring dendrite and axon length in primary neuronal cell cultures treated with ketamine and lithium.Results: Ketamine decreased DISC1 in a dose and time-dependent manner. This corresponded to decreases in phosphorylated GSK-3β, which implicates increased GSK-3β activity. Lithium significantly attenuated ketamine-induced decrease in DISC1 levels. Ketamine decreased coimmunoprecipitation of DISC1 with GSK-3β and axonal length Conclusions: These findings confirmed that acute administration of ketamine decreases in DISC1 levels and axonal growth. Lithium reversed this effect. This interaction provides a link between DISC1 and ketamine-induced neurodegeneration.