2022, Vol. 26 ›› Issue (20): 3230-3235

Effects of time-specific AMP-activated protein kinase alpha1/2 gene knockout on hippocampal energy metabolism and synaptic plasticity in mice

Liu Yulu1, Jia Weiwei1, 2, Dai Yaling1, Xu Wenshan1, Ding Yanyi1, Liang Shengxiang3, Liu Weilin2, 3, Chen Lidian2   

Abstract: BACKGROUND: AMP-Activated protein kinase (AMPK) is a molecular-level energy sensor that can be activated when the body is in a low energy state to provide energy for neuronal activity. However, the relationship between time-specific AMPK knockout and the development of cognitive dysfunction remains unclear.
OBJECTIVE: To investigate the effects of time-specific AMPKα1/2 knockout on hippocampal energy metabolism and synaptic plasticity in mice, and to search for key molecular targets between energy metabolism and cognitive function.
METHODS: Sixteen 6-month-old mice with AMPKα1/2FLOX/FLOX and AMPKα1/2FLOX/FLOX+Camk2a-cre/ERT2 were randomly divided into control group (n=8) and AMPKα1/2 knockout group (n=8). The AMPKα1/2 knockout group was intraperitoneally injected with 0.1 mL tamoxifen daily, while the control group was intraperitoneally injected with an equal dose of corn oil solvent daily. Injections in each group were conducted for 5 continuous days. After 7 days, Barnes maze test was used to test spatial learning and memory ability of mice. Chemical exchange saturation transfer imaging was used to observe the glucose metabolism in the hippocampus. Patch clamp electrophysiological techniques were used to detect the field potential of hippocampal CA3-CA1 neural circuit, including input-output curve, paired-pulse facilitation ratio and long-term synaptic plasticity induced by high frequency stimulation.
RESULTS AND CONCLUSION: Compared with the control group, the escape latency was prolonged (P < 0.001), the frequency of contact with the target hole decreased significantly (P < 0.05), and the time spent in the target quadrant decreased significantly (P < 0.05) in the AMPKα1/2 knockout group. Compared with the control group, the level of glucose metabolism in the hippocampus of mice was reduced in the AMPKα1/2 knockout group (P < 0.05). Compared with the control group, the voltage in the hippocampus was significantly decreased with different amounts of stimulation in the AMPKα1/2 knockout group (P < 0.05). At the base field potential, the paired-pulse facilitation ratios at different time intervals decreased significantly (P < 0.05). Compared with the control group, high frequency stimulation significant reduced the amplitude of excitatory postsynaptic potential in the hippocampus of mice in the AMPKα1/2 knockout group after (P < 0.05). These results suggest that time-specific AMPKα1/2 knockdown decreases glucose metabolism in the hippocampus, impairs presynaptic transmitter release, synaptic transmission efficiency, and synaptic plasticity, thereby leading to spatial learning and memory disorders.
Key words: AMP-Activated protein kinase, mouse, glucose metabolism, synaptic transmission efficiency, synaptic plasticity, long-term potentiation, learning and memory