MARCKSL1 regulates spine formation and controls anxiety

Abnormalities in the limbic neural circuits have been implicated in the onset of anxiety disorders. However, the molecular pathogenesis underlying anxiety disorders remains poorly elucidated. Here, we demonstrate that myristoylated alanine-rich C-kinase substrate like 1 (MARCKSL1) regulates the amygdala circuitry to control the activity of hypothalamic-pituitary-adrenal (HPA) axis and induces anxiety behaviors in mice. MARCKSL1 expression was predominantly localized in the prefrontal cortex (PFC), hypothalamus, hippocampus, and amygdala of the adult mouse brain. MARCKSL1 transgenic (Tg) mice exhibited anxiety-like behaviors dependent on corticotropin releasing hormone. MARCKSL1 increased the spine formation in the central amygdala, and the downregulation of MARCKSL1 in the amygdala normalized both increased activity of the HPA axis and elevated anxiety-like behaviors in Tg mice. Furthermore, there was increased MARCKSL1 expression in the PFC and amygdala in a brain injury model associated with anxiety-like behaviors. Our findings suggest that MARCKSL1 expression in the amygdala plays an important role in anxiety-related behaviors.边缘神经环路（limbic neural circuits）异常已被证实与焦虑障碍的发病相关。然而，焦虑障碍背后的分子发病机制仍未得到充分阐明。本研究证实，富含丙氨酸的豆蔻酰化蛋白激酶C底物样蛋白1（myristoylated alanine-rich C-kinase substrate like 1, MARCKSL1）可调控杏仁核（amygdala）环路，进而控制下丘脑-垂体-肾上腺（hypothalamic-pituitary-adrenal, HPA）轴的活性，并诱发小鼠的焦虑样行为。MARCKSL1的表达主要定位于成年小鼠脑内的前额叶皮层（prefrontal cortex, PFC）、下丘脑、海马体（hippocampus）与杏仁核。MARCKSL1转基因（transgenic, Tg）小鼠可表现出依赖促肾上腺皮质激素释放激素（corticotropin releasing hormone）的焦虑样行为。MARCKSL1可促进中央杏仁核（central amygdala）的树突棘形成；而在转基因小鼠的杏仁核中下调MARCKSL1的表达，可同时使亢进的HPA轴活性与升高的焦虑样行为恢复正常。此外，在伴有焦虑样行为的脑损伤模型中，小鼠前额叶皮层与杏仁核内的MARCKSL1表达水平显著升高。本研究结果表明，杏仁核内的MARCKSL1表达在焦虑相关行为中发挥关键作用。