GluN2A Mediates PS-Induced Depressive-Like Behavior by Activating CaMKII and Inhibiting Myelinization
Huimei Huang1,2, Hongli Jiang1, Hongli Sun3
1The Department of Blood Purification, The First Affiliated Hospital of Xi'an Jiaotong University, 710061 Xi'an, Shaanxi, China.
Insights
Prenatal stress (PS) in rats leads to depression-like behaviors in offspring by altering hippocampal glutamate levels and impairing myelinization. Targeting GluN2A receptors shows promise for treating this condition.
Area of Science:
- Neuroscience
- Developmental Psychology
- Pharmacology
Background:
- Prenatal stress (PS) is linked to offspring depression, but the exact mechanisms remain unclear.
- Understanding these mechanisms is crucial for developing effective interventions.
Purpose of the Study:
- To investigate the neurobiological mechanisms underlying prenatal stress-induced depressive-like behavior in offspring.
- To identify potential therapeutic targets for prenatal stress-related depression.
Main Methods:
- A rat model of prenatal restraint stress (GD14-GD20) was used.
- Depressive-like behaviors were assessed via sucrose preference and forced swim tests.
- Hippocampal levels of glutamate, GluN2A, p-CaMKII, and myelin basic protein (MBP) were analyzed.
Main Results:
- Prenatal stress significantly elevated hippocampal glutamate and altered GluN2A and p-CaMKII expression in susceptible offspring.
- Impaired myelinization was observed, indicated by decreased MBP levels.
- Treatment with a GluN2A antagonist (NVP-AAM077) reversed depressive-like behaviors and normalized MBP and p-CaMKII levels.
Conclusions:
- Prenatal stress induces depression-like behaviors through mechanisms involving hippocampal glutamate dysregulation and impaired myelinization.
- The GluN2A receptor is a potential therapeutic target for pharmacotherapies aimed at treating prenatal stress-induced depression.
Background:
Prenatal stress (PS) can induce depression in offspring, but the underlying mechanisms are still unknown.
Objective:
The aim of this work was to investigate the mechanism that underlies PS-induced depressive-like behavior in offspring.
Methods:
A prenatal restraint stress procedure was developed in which pregnant rats at GD14 to GD20 were placed head-first into a well-ventilated bottle three times each day and for 45 min each time. Depressive-like behavior in the male offspring was examined using the sucrose preference test (SPT) and the forced swim test (FST). The level of glutamate and the expression levels of GluN2A, p-CaMKII and myelin basic protein (MBP) in the hippocampus of PS-susceptible (PS-S) offspring were also evaluated. To clarify the mechanism by which PS leads to depression in offspring, the effects of excessive corticosterone were also investigated using an in vitro "injured neuronal" model.
Results:
The glutamate level in the hippocampus of PS-S male offspring was significantly elevated compared to controls. The expression levels of GluN2A and p-CaMKII were also altered. In addition, the optical density of MBP staining and the expression levels of MBP mRNA and MBP protein were decreased, demonstrating impaired myelinization in the hippocampus. Treatment of PS-S offspring with the GluN2A receptor antagonist NVP-AAM077 resulted in antidepressant-like effects in the FST, as well as rescue of the MBP and p-CaMKII abnormalities.
Conclusions:
These findings indicate that GluN2A is a promising target in the development of pharmacotherapies for PS-induced depression.
