Effects of ADAM10 deletion on Notch-1 signaling pathway and neuronal maintenance in adult mouse brain

Abstract

A disintegrin and metalloproteinase 10 (ADAM10) has been demonstrated to regulate embryonic brain development by initiating Notch signaling. However, it is still unclear whether ADAM10 is required to activate the Notch signaling pathway in adult brain. To investigate the physiological role of ADAM10, we generated conditional knockout (cKO) mice lacking the Adam10 gene primarily in the cortex and hippocampus. We found that conditional disruption of ADAM10 resulted in a prominent decrease in the number of proliferating neuronal progenitor cells in the subgranular zone (SGZ), and a significant increase in the number of adult-generated postmitotic neurons in the hippocampal dentate gyrus (DG) due to premature neuronal differentiation. Moreover, the mutant mice also displayed an age-dependent reduction in the number of granule neurons in the hippocampal DG. It was further showed that the activation of Notch-1 and its downstream target genes Hes1, Hes5, Hey1, and Hey2 was impaired in ADAM10-deficient hippocampal tissues. Finally, Adam10 cKO mice had impaired learning and memory in the Morris water-maze. Thus, we provided experimental evidence to demonstrate that ADAM10 plays an essential role in the activation of Notch-1 signaling and has a remarkable effect on neuronal maintenance in adult mouse brain.