Rab18在成年神經元新生和育幼行為中所扮演的角色

Abstract

Rab蛋白質屬於Ras相關的小GTP水解酶家族的一員。已知Rab蛋白質功能為調控胞囊運輸，有研究指出Rab18在神經內分泌細胞中為負調控因子，但是Rab18在成年的神經系統中所辦演的角色仍未被研究。在成年哺乳動物的腦中，仍有兩處有神經元新生，一處在嗅球，另一處在齒狀迴。成年神經元新生在嗅球的功能為分辨一般氣味和調控天生的嗅覺反應，如配偶的辨認和育幼行為；另一方面，成年神經元新生在齒狀迴的功能為抗憂鬱反應和海馬迴相關的學習與記憶。有趣的是，Rab18突變的雌鼠有嚴重的育幼行為缺損和無法辨認子代，這個缺陷如同沒有成年神經元新生的雌鼠，這顯示Rab18可能對於成年神經元新生非常重要。我們用BrdU標定新生的細胞，發現Rab18突變的雌鼠在嗅球的成年神經元新生降低，並且發現在齒狀迴顆粒細胞下區和側腦室下區的神經幹細胞、神經母細胞密度和它們的增生也比正常野生雌鼠低。此外，我們也發現Rab18突變的雌鼠嗅球和黑質內的多巴胺濃度上升。由於已知多巴胺會抑制成年神經元新生，這些結果表示Rab18可能透過抑制多巴胺釋放來調控成年神經元新生。Rab proteins belonging to Ras-related small GTPase superfamily are regulators of vesicle trafficking. Rab18 has been shown to act as a negative regulator of the secretory pathway in neuroendocrine cells. However, the role of Rab18 in the adult nervous system has not been studied. In the mammalian brain, adult neurogenesis occurs continuously in the olfactory bulb (OB) and the dentate gyrus (DG). The function of adult neurogenesis in the OB has been implicated in odor discrimination and innate pheromonal responses, such as mate recognition and maternal behaviors. On the other hand, adult neurogenesis in the DG is involved in antidepressant effects and hippocampal-dependent learning and memory. Interestingly, Rab18 null female mice have impaired maternal behaviors and pup recognition, which are the same behavior defects in female mice when their adult neurogenesis is blocked. This suggests that Rab18 may play important roles in adult neurogenesis. By BrdU, a thymidine analog, injection to label newborn cells, we observed that adult neurogenesis in the OB was decreased in Rab18 null female mice. Moreover, progenitor cells in the neural stem cell niche and cell proliferation in the SGZ and SVZ of Rab18 null female mice were also decreased. In addition, we found that there was a trend increase in the level of dopamine in the OB and substantia nigra (SN) in middle-aged adult Rab18 null female mice. Since dopamine has been known to inhibit adult neurogenesis, these results suggest that Rab18 may regulate adult neurogenesis through inhibiting dopamine release.