Abstract:

Objective To investigate the effects of dihydrotestosterone (DHT) on spatial learning and memory and synaptic plasticity in hippocampus of SAMP8 male mice under continuous hypoxia, and to understand the effect of androgen on hippocampal synaptic plasticity in rapidly aging mice. 

Methods Forty healthy adult (5-month-old) male SAMP8 mice were randomly divided into Control group, DHT group, Hypoxia group, and DHT+Hypoxia group, with 8 mice in each group. Morris water maze was used to detect the spatial learning and memory abilities of mice. Golgi-cox staining was used to detect the density changes of synaptic dendritic spine in hippocampal CA1. RT-PCR and Western blot were used to detect the expression of related genes and proteins. 
Results The escape latency of the Hypoxia group was significantly longer than that of the Control group, while the escape latency of the DHT group was significantly shorter than that of the Control group and the Hypoxia group (P＜0.05). The target quadrant time in the DHT group was significantly longer than that in the Control group, and the number of crossing platform was significantly greater than that in the Control group (P＜0.05). The density of synaptic dendritic spine in hippocampal CA1 region in the DHT group and the DHT+Hypoxia group was significantly higher than that in Control group and the Hypoxia group (P＜0.05). Hif-1α, Epo and Epor expression of Hypoxia group was higher than that of the Control group, while the expression of Glut1, Syn, Psd-95, and Drebrin was lower than that of the Control group. The expression of Hif-1α, Erk, Glut1, Syn, Psd-95, and Drebrin genes in the DHT group was higher than that of the Control group, while the expression of Hif-1α and Epo gene of  the DHT+Hypoxia group was higher than that of the Control group (P＜0.05). Hif-1α and Epo expression in DHT group was lower than that in Hypoxia group, and Erk, Glut1, Syn, Psd-95, and Drebrin expression was higher than that in Hypoxia group; Hif-1α was lower in the DHT+Hypoxia group than that in the Hypoxia group, and Glut1, Syn, Psd-95, and Drebrin expression was higher than that in the Hypoxia group (P＜0.05). The protein expression of ERK, pERK, Glut1, and PSD95 was lower in the Hypoxia group than in the Control group, while Iba1 was higher than that in the Control group. The protein expression of ERK, pERK, Glut1, PSD95, Drebrin, SYN, and Iba1 in the DHT group was higher than that in the Control group, and the protein expression of ERK, pERK, Glut1, PSD95, and Iba1 in the DHT+Hypoxia group was higher than in the Control group (P＜0.05). The expression of ERK, pERK, Glut1, PSD95, Drebrin, and SYN proteins in the DHT group was higher than that in the Hypoxia group, while the expression of Iba1 protein was lower than that in the Hypoxia group. The expression of ERK, pERK, Glut1, and PSD95 proteins in the DHT+Hypoxia group was higher than that in the Hypoxia group (P＜0.05). 
Conclusion Dihydrotestosterone can promote the synaptic plasticity of hippocampal neurons and improve the spatial learning and memory abilities via  HIF-1α, ERK and GLUT1 signaling pathways. 

Key words: cognitive dysfunction, dihydrotestosterone, spatial learning, hypoxia