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Glutamate and GABA imbalance promotes neuronal apoptosis in hippocampus after stress

Jie Gao, He Wang, Yuan Liu, Ying-yu Li, Can Chen, Liang-ming Liu, Ya-min Wu, Sen Li, Ce Yang

State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, China (mainland)

Med Sci Monit 2014; 20:499-512

DOI: 10.12659/MSM.890589

Available online:

Published: 2014-03-27

Background: People who experience traumatic events have an increased risk of post-traumatic stress disorder (PTSD). However, PTSD-related pathological changes in the hippocampus and prefrontal cortex remain poorly understood.
Material and Methods: We investigated the effect of a PTSD-like animal model induced by severe stress. The experimental rats received 20 inescapable electric foot shocks in an enclosed box for a total of 6 times in 3 days. The physiological state (body weight and plasma corticosterone concentrations), emotion, cognitive behavior, brain morphology, apoptosis, and balance of gamma-aminobutyric acid (GABA) and glutamate in the hippocampus and prefrontal cortex were observed. Cell damages were examined with histological staining (HE, Nissl, and silver impregnation), while apoptosis was analyzed with flow cytometry using an Annexin V and propidium iodide (PI) binding and terminal deoxynucleotidyl transferase mediated-dUTP nick end labeling (TUNEL) method.
Results: In comparison with the sham litter-mates, the stressed rats showed decreased body weight, inhibition of hypothalamic-pituitary-adrenal (HPA) axis activation, increase in freezing response to trauma reminder, hypoactivity and anxiety-like behaviors in elevated plus maze and open field test, poor learning in Morris water maze, and shortened latency in hot-plate test. There were significant damages in the hippocampus but not in the prefrontal cortex. Imbalance between glutamate and GABA was more evident in the hippocampus than in the prefrontal cortex.
Conclusions: These results suggest that neuronal apoptosis in the hippocampus after severe traumatic stress is related to the imbalance between glutamate and GABA. Such modifications may resemble the profound changes observed in PTSD patients.

Keywords: Anxiety - pathology, Animals, Apoptosis - drug effects, Behavior, Animal - drug effects, Body Weight - drug effects, Dexamethasone - pharmacology, Emotions, Freezing Reaction, Cataleptic - drug effects, Glutamic Acid - metabolism, Hippocampus - pathology, Hypothalamo-Hypophyseal System - pathology, In Situ Nick-End Labeling, Maze Learning - drug effects, Neurons - pathology, Pituitary-Adrenal System - pathology, Prefrontal Cortex - pathology, Rats, Rats, Sprague-Dawley, Reaction Time - drug effects, Stress Disorders, Post-Traumatic, Stress, Psychological - pathology, gamma-Aminobutyric Acid - metabolism