Notch1 not only plays a key role in the development of the nervous system but also modulates synaptic plasticity and memory. However, the role of Notch1 in the brain of diabetes is still unclear. We hypothesize that Notch1 is involved in type I diabetes-induced cognitive dysfunction. In this study, adult male C57BL/6J mice carrying a heterozygous null mutation in the Notch1 gene (Notch1+/-) and wild-type littermate controls were used in this experiment. They were subjected to streptozocin (55 mg/kg, i.p.) for consecutive five days. After 12 weeks, the cognitive function of all mice was detected by novel object recognition (NOR) test and electrophysiological recording. Our results demonstrated that the levels of Notch1 mRNA and Notch1 receptor were increased in the hippocampus of the wild-type diabetic mice at 12 weeks. It suggested that the Notch1 signal pathway was activated. Compared with the wild-type diabetic mice, the discrimination index and the long-term potentiation was further decreased in the Notch1+/- diabetic group, the impairment of neuronal ultrastructure was exacerbated in the hippocampus of the Notch1+/- diabetic mice, and the number of synapses and autophagic vacuoles were significantly reduced in the Notch1+/- diabetic group. Moreover, some postsynaptic associated protein expressions were down-regulated, as well as the Beclin1 expression and the ratio of LC3II/LC3I were reduced in the hippocampus of the Notch1+/- diabetic mice. Interestingly, the phosphorylation of mTOR, Akt, and ERK1/2 were all inhibited in the Notch1+/- diabetic group. Taken together, these results suggest that Notch1 deficiency deteriorates the synaptic plasticity and inhibits the activation of autophagy partly via the mTOR-independent signal pathway in the hippocampus of type I diabetic mice.
Keywords: Autophagy; Cognitive function; Diabetes mellitus; Hippocampus; Notch1.
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