Impaired synaptic plasticity and decreased excitability of hippocampal glutamatergic neurons mediated by BDNF downregulation contribute to cognitive dysfunction in mice induced by repeated neonatal exposure to ketamine

• DOI: 10.1111/cns.14604
• Publication Date: 2024-02-09T06:53:16Z
• Authors: Jie Wan; Linhui Ma; Xinhao Jiao; Wei Dong; Jiatao Lin; Yongkang Qiu; Weifeng Wu; Qiang Liu; Chen Chen; He Huang; Shuai Li; Hui Zheng; Yuqing Wu
• Keywords: 0303 health sciences; 03 medical and health sciences; Original Articles

AbstractAimRepeated exposure to ketamine during the neonatal period in mice leads to cognitive impairments in adulthood. These impairments are likely caused by synaptic plasticity and excitability damage. We investigated the precise role of brain‐derived neurotrophic factor (BDNF) in the cognitive impairments induced by repeated ketamine exposure during the neonatal period.MethodsWe evaluated the cognitive function of mice using the Morris water maze test and novel object recognition test. Western blotting and immunofluorescence were used to detect the protein levels of BDNF. Western blotting, Golgi‐Cox staining, transmission electron microscopy, and long‐term potentiation (LTP) recordings were used to assess synaptic plasticity in the hippocampus. The excitability of neurons was evaluated using c‐Fos. In the intervention experiment, pAdeno‐CaMKIIα‐BDNF‐mNeuronGreen was injected into the hippocampal CA1 region of mice to increase the level of BDNF. The excitability of neurons was enhanced using a chemogenetic approach.ResultsOur findings suggest that cognitive impairments in mice repeatedly exposed to ketamine during the neonatal period are associated with downregulated BDNF protein level, synaptic plasticity damage, and decreased excitability of glutamatergic neurons in the hippocampal CA1 region. Furthermore, the specific upregulation of BDNF in glutamatergic neurons of the hippocampal CA1 region and the enhancement of excitability can improve impaired synaptic plasticity and cognitive function in mice.ConclusionBDNF downregulation mediates synaptic plasticity and excitability damage, leading to cognitive impairments in adulthood following repeated ketamine exposure during the neonatal period.