Altered GSK3β signaling in an infection-based mouse model of developmental neuropsychiatric disease

Abstract

Protein kinase B (AKT) and glycogen synthase kinase 3 beta (GSK3β) are two protein kinases involved in dopaminergic signaling. Dopamine-associated neuropsychiatric illnesses such as schizophrenia and bipolar disorder seem to be characterized by impairments in the AKT/GSK3β network. Here, we sought evidence for the presence of molecular and functional changes in the AKT/GSK3β pathway using an established infection-based mouse model of developmental neuropsychiatric disease that is based on prenatal administration of the viral mimetic poly(I:C) (=polyriboinosinic–polyribocytidilic acid). We found that adult offspring of poly(I:C)-exposed mothers displayed decreased total levels of AKT protein and reduced phosphorylation at AKT threonine residues in the medial prefrontal cortex. Prenatally immune challenged offspring also exhibited increased GSK3β protein expression and activation status, the latter of which was evidenced by a decrease in the ratio between phosphorylated and total GSK3β protein in the medial prefrontal cortex. These molecular changes were not associated with overt signs of inflammatory processes in the adult brain. We further found that acute pre-treatment with the selective GSK3β inhibitor TDZD-8 dose-dependently normalized aberrant behavior typically emerging following prenatal immune activation, including deficient spontaneous alternation in the Y-maze and increased locomotor responses to systemic amphetamine treatment. Taken together, the present mouse model demonstrates that prenatal exposure to viral-like immune activation leads to long-term alterations in GSK3β signaling, some of which are critically implicated in schizophrenia and bipolar disorder.