Maternal deprivation induces cytoskeletal alterations and depressive-like behavior in adult male rats by regulating the AKT/GSK3β/CRMP2 signaling pathway

Abstract

Early-life adverse events exert persistent effects on brain functions and may increase the risk of psychopathology in adulthood. However, the underlying mechanism remains unclear. The purpose of our study was to study the long-lasting effects of maternal deprivation (MD) on depression-related behaviors and microtubule dynamics, and to illuminate the underlying molecular mechanism. Rat pups were separated from the dams for 360 min (MD) or 15 min (brief maternal separation) each day from postnatal day 4 through 10. Rats with MD experience showed significant depressive-like behaviors in adulthood, while brief maternal separation did not alter the behaviors. Behavioral alterations in the MD group were accompanied by alterations in the AKT/GSK3β/CRMP2 signaling pathway and hyperphosphorylation of CRMP2. CRMP2 interacted and colocalized with the cytoskeleton in the hippocampus, and the overlap of CRMP2 and tubulin staining in the hippocampus of MD rats was decreased. In MD rats, the expression of the α-tubulin isoforms Acet-tubulin and Tyr-tubulin changed, and the ratio of Tyr/Acet-tubulin, which is an important marker of microtubule dynamics, was decreased, indicating decreased microtubule dynamics. Furthermore, regulation of the AKT/GSK3β/CRMP2 signaling pathway by an LY294002 microinjection in the hippocampus resulted in cytoskeletal alterations and depressive-like behaviors in rats. These findings suggest that early-life MD induces depressive-like behaviors and cytoskeletal alterations in adult male rats and that the effects may be partly mediated by the AKT/GSK3β/CRMP2 signaling pathway. An understanding of the mechanism underlying the effect of MD on behaviors is crucial for developing pharmacological and psychological interventions for childhood neglect.