Synaptic remodeling and reduced expression of the transcription factors, HES1 and HES5, in the cortex neurons of cognitively impaired hyperhomocysteinemic mice

Abstract

Hyperhomocysteinemia (HHcy) is associated with cognitive impairment and neurodegenerative diseases. The synaptic ultrastructure and the expression of hairy enhancer of split (HES) genes are involved in cognitive impairment induced by HHcy, but their precise role remains unclear. The present study aimed to measure synaptic remodeling and the expression of HES1 and HES5 in the cortex neurons of mice with HHcy to clarify their role in cognitive impairment. Mild HHcy was induced in ApoE−/− mice receiving a high-methionine diet. The correct response percentage, latency, and distance traveled in the mice with HHcy decreased compared with those of non-HHcy control mice (P < 0.05). There was no difference in the neuronal counts and the mean optical density of Nissl bodies in the frontal cortex of HHcy and non-HHcy mice. Increased apoptosis rates and numbers of autophagosomes were observed in the HHcy mice by TUNEL staining and electron microscopy, respectively, compared to those in the control group (P < 0.05). There was a significant increase in the area of postsynaptic density and size variation of synaptic vesicles in the HHcy group compared to that in the control (P < 0.05). Decreased expression of HES1 and HES5 was observed by western blotting and immunostaining in the HHcy group compared to that in the control (P < 0.05). Collectively, these results suggest that increased autophagy, apoptosis, synaptic remodeling, and downregulation of hes1 and hes5 are involved in the cognitive impairment induced by hyperhomocysteinemia.