Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, 10010 N Torrey Pines Road, La Jolla, CA, 92037, USA.
Department of Neuroscience, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA, 19107, USA.
Sci Rep. 2022 Mar 9;12(1):4176. doi: 10.1038/s41598-022-08031-4.
Ischemic injury occurs when the brain is deprived of blood flow, preventing cells from receiving essential nutrients. The injury core is the brain region directly deprived and is surrounded by the peri-infarct area, the region with recovery potential. In the peri-infarct area neurons undergo acute loss of dendritic spines, which modifies synaptic plasticity and determines neuronal survival. Astrocytes can be protective or detrimental to the ischemic injury response depending on the specific stage, yet we lack clear understanding of the underlying mechanisms. Chordin-like 1 (Chrdl1) is an astrocyte-secreted protein that promotes synaptic maturation and limits experience-dependent plasticity in the mouse visual cortex. Given this plasticity-limiting function we asked if Chrdl1 regulates the response to ischemic injury, modelled using photothrombosis (PT). We find that Chrdl1 mRNA is upregulated in astrocytes in the peri-infarct area in both acute and sub-acute phases post-PT. To determine the impact of increased Chrdl1 on the response to PT we analyzed Chrdl1 knock-out mice. We find that absence of Chrdl1 prevents ischemia-induced spine loss in the peri-infarct area and reduces cell death in the core, without impacting gliosis. These findings highlight the important role of astrocyte-secreted proteins in regulating structural plasticity in response to brain ischemic injuries.
当大脑血流被阻断时，就会发生缺血性损伤，从而阻止细胞接收必要的营养物质。损伤核心是直接被剥夺的大脑区域，周围是具有恢复潜力的梗死周边区域。在梗死周边区域，神经元会急性丧失树突棘，这会改变突触可塑性并决定神经元的存活。星形胶质细胞对缺血性损伤反应可能具有保护作用，也可能具有损害作用，具体取决于特定的阶段，但我们对其潜在机制缺乏清晰的认识。Chordin-like 1 (Chrdl1) 是一种星形胶质细胞分泌的蛋白，可促进突触成熟并限制小鼠视觉皮层中与经验相关的可塑性。鉴于这种限制可塑性的功能，我们想知道 Chrdl1 是否调节缺血性损伤的反应，使用光血栓形成 (PT) 来模拟。我们发现，在 PT 后急性和亚急性阶段，Chrdl1 mRNA 在梗死周边区域的星形胶质细胞中上调。为了确定增加的 Chrdl1 对 PT 反应的影响，我们分析了 Chrdl1 敲除小鼠。我们发现，Chrdl1 的缺失可防止梗死周边区域缺血引起的棘突丧失，并减少核心中的细胞死亡，而不会影响神经胶质增生。这些发现强调了星形胶质细胞分泌蛋白在调节大脑缺血性损伤后结构可塑性中的重要作用。
