Department of Histology and Embryology, Army Medical University, Chongqing 400038, China.
Department of Histology and Embryology, Army Medical University, Chongqing 400038, China..
Exp Neurol. 2019 Nov;321:113034. doi: 10.1016/j.expneurol.2019.113034. Epub 2019 Aug 12.
Depression is the most common comorbidity among patients with epilepsy. Despite prior assumptions that antiepileptic drugs are to blame, more and more pathological studies have shown that latent neurological alterations associated with white matter injury and demyelination may underlie this link. However, whether disturbances in cerebral myelination contribute to the initiation of depression in epilepsy remains unclear. In the present study, we investigated the connection between demyelination disorders and the development of depression comorbidity in epilepsy. We first induced spontaneous recurrent epilepticus seizure (SRS) in young rats with pilocarpine. We then established depressive behaviors by recurrent forced swimming test and evaluate the depression state by sucrose preference test. The ratio of depression comorbidity in SRS rats was then calculated. Next, myelination in SRS-Depressed (SRS-D) rats was explored via PCR, western blotting, and immunohistochemistry for the key myelin promotion factor, Olig2 and inhibition factor, LINGO-1. Finally, in situ RNA hybridization of NCX3, one of the dominant Ca extrusion proteins in oligodendrocytes (OLs) was performed to explore whether Ca homeostasis of OLs was disturbed in epilepsy-induced hypoxic conditions and involved in the epilepsy-depression comorbidity. Our results revealed that one-quarter of the SRS rats displayed typical depressive behaviors, which were defined as SRS-D rats. In SRS-D rats, severe demyelination was also observed, accompanied with reduced expression of MBP, Olig2, and NCX3 and increased expression of LINGO-1 in the cingulate gyrus. In SRS-Non depressed rats, no significant changes were found from the control animals. This work provides new insights into the demyelination in epilepsy-depression comorbidity, which involves dysregulation of Olig2/LINGO-1 and disturbance of Ca homeostasis.
抑郁症是癫痫患者最常见的合并症。尽管先前的假设认为抗癫痫药物是罪魁祸首，但越来越多的病理学研究表明，与白质损伤和脱髓鞘相关的潜在神经改变可能是这种联系的基础。然而，大脑髓鞘的紊乱是否导致癫痫中抑郁的发生仍不清楚。在本研究中，我们研究了脱髓鞘紊乱与癫痫并发抑郁症之间的关系。我们首先用匹罗卡品诱导年轻大鼠发生自发性反复癫痫发作（SRS）。然后通过反复强迫游泳试验建立抑郁行为，并通过蔗糖偏好试验评估抑郁状态。计算 SRS 大鼠中抑郁共病的比例。接下来，通过 PCR、western blot 和免疫组织化学检测关键髓鞘促进因子 Olig2 和抑制因子 LINGO-1，研究 SRS 抑郁（SRS-D）大鼠的髓鞘形成。最后，通过原位 RNA 杂交检测 NCX3，NCX3 是少突胶质细胞（OLs）中一种主要的 Ca 外排蛋白，以探讨在癫痫诱导的缺氧条件下 OLs 的 Ca 稳态是否受到干扰，并参与癫痫-抑郁共病。我们的研究结果表明，四分之一的 SRS 大鼠表现出典型的抑郁行为，被定义为 SRS-D 大鼠。在 SRS-D 大鼠中，还观察到严重的脱髓鞘，同时在扣带回中观察到 MBP、Olig2 和 NCX3 的表达减少，LINGO-1 的表达增加。在 SRS 非抑郁大鼠中，与对照组相比，没有发现明显的变化。这项工作为癫痫-抑郁共病中的脱髓鞘提供了新的见解，涉及 Olig2/LINGO-1 的失调和 Ca 稳态的紊乱。
