癫痫持续状态后树突内F-actin杆状聚集的成因及细胞骨架-内体-溶酶体途径引发神经元死亡的机制

After status epilepticus, some neurons in the brain are destined for death after a silent period, but the underlying mechanisms are still unknown. Before death, the dendritic spines of impaired neurons are seriously reduced, and the F-actin cytoskeleton within the spines becomes progressively depolymerized. We recently found that F-actin was transiently aggregated into rod-like structures in the dendritic shafts after its disappearance from the dendritic spines. Since F-actin is anchored to the microtubules within the dendritic shafts, we propose that the depolymerization and rod-like aggregation of F-actin may be due to the decontruction of dendritic microtubules. Moreover, the excitotoxic damage due to status epilepticus results in abnormally enhancement of endocytosis, and the rod-like aggregation of F-actin may be partially related to the translocation of endosome-associated F-actin into dendrites. Since the formation and transport of endosomes rely highly on the intact cytoskeletons, the depolymerization of F-actin and microtubules may result in damages to the endosome-lysosome system, and ultimately lead to neuronal death. This project is aimed to investigate the origins of the rod-like accumulation of dendritic F-actin and make clear the mechanisms of neuronal death by the cytoskeleton-endosome-lysosome pathway after status epilepticus, by which we hope to provide a new theoretical basis for epilepsy treatment.

癫痫持续状态后脑内神经元出现迟发性死亡，其机制尚不清楚。神经元死亡之前，树突棘广泛缺失，树突棘内F-actin骨架发生不可逆性解聚。我们发现F-actin从树突棘消失后会短暂聚集在树突干内形成特殊的杆状结构。以此为线索，我们注意到癫痫脑内F-actin损伤、微管解聚和内体-溶酶体异常三种现象共存并相互影响。树突干内微管解聚使F-actin丧失了锚定和调节位点，可能是树突棘塌陷和F-actin杆状聚集的主要原因；另一方面，癫痫放电后突触后膜内吞活动增强，F-actin随着内吞小泡进入树突内也会导致树突干F-actin聚集现象。更重要的是，内吞物质从内体到溶酶体的转运过程高度依赖F-actin和微管，后两者解聚势必会导致内体-溶酶体功能紊乱引发神经元死亡。因此，本项目拟采用体内外实验阐明树突干内F-actin杆状聚集的成因，探讨F-actin和微管解聚通过内体-溶酶体途径引起神经元死亡的机制。