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Effect of ketamine on mood dysfunction and spatial cognition deficits in PTSD mouse models via HCN1-BDNF signaling
Xianqiang Zhang1, Yanan Zhao2, Yalin Du3
1School of Psychology, Weifang Medical University, 7166# Baotong West Street, Weifang, Shandong 261053, China; National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital/Institute of Mental Health and the Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
Background:
Post-traumatic stress disorder (PTSD) is a debilitating mental disease with high morbidity and major social and economic relevance. No efficient treatment for PTSD has thus far been identified. Clinical research has shown that ketamine can rapidly alleviate symptoms in patients with chronic PTSD; however, its pharmacological mechanism has yet to be determined.
Methods:
This study aimed to identify a model of single prolonged stress (SPS), which induced PTSD-like features in adult mice. Once the model was established, stress-related behavioral changes in the mouse model were evaluated after intraperitoneal injection of ketamine (10 mg/kg). Alterations in certain proteins (HCN1, BDNF, and PSD95) and synaptic ultrastructure in the prefrontal cortex (PFC) and hippocampus (HIP) were measured.
Results:
The mice under the SPS model exhibited anxiety- and depression-like behaviors and induced spatial cognitive deficits, accompanied by elevated HCN1 protein expression in the PFC and HIP, reduced brain-derived neurotrophic factor (BDNF) and PSD95 proteins, and alterations in synaptic morphology. After ketamine administration, the SPS-treated mice restored their protein levels and synaptic ultrastructure in the PFC, and their PTSD-like behaviors improved. However, learning and memory in the SPS-treated mice did not improve in the water maze test, and no significant changes in protein level and synaptic ultrastructure in the HIP were shown.
Limitations:
The electrophysiological mechanism of the HCN1 ion channel after ketamine administration was not explored.
Conclusion:
Ketamine could generally improve SPS-induced mood dysfunction in mice but exerted no effect on the spatial cognitive function, which could be related to the alterations in synaptic morphology and function mediated by HCN1-related BDNF signaling in the PFC and HIP.
