Repetitive Diffuse Mild Traumatic Brain Injury Causes An Atypical Astrocyte Response and Spontaneous Recurrent Seizures Shandra O, Winemiller AR, Heithoff BP, et al. J Neurosci. 2019;39(10):1944-1963. doi:10.1523/JNEUROSCI.1067-18.2018. Epub 2019 Jan 21. PMID: 30665946 . Focal traumatic brain injury (TBI) induces astrogliosis, a process essential to protecting uninjured brain areas from secondary damage. However, astrogliosis can cause loss of astrocyte homeostatic functions and possibly contributes to comorbidities such as posttraumatic epilepsy (PTE). Scar-forming astrocytes seal focal injuries off from healthy brain tissue. It is these glial scars that are associated with epilepsy originating in the cerebral cortex and hippocampus. However, the vast majority of human TBIs also present with diffuse brain injury caused by acceleration-deceleration forces leading to tissue shearing. The resulting diffuse tissue damage may be intrinsically different from focal lesions that would trigger glial scar formation. Here, we used mice of both sexes in a model of repetitive mild/concussive closed-head TBI, which only induced diffuse injury, to test the hypothesis that astrocytes respond uniquely to diffuse TBI and that diffuse TBI is sufficient to cause PTE. Astrocytes did not form scars and classic astrogliosis characterized by upregulation of glial fibrillary acidic protein was limited. Surprisingly, an unrelated population of atypical reactive astrocytes was characterized by the lack of glial fibrillary acidic protein expression, rapid and sustained downregulation of homeostatic proteins, and impaired astrocyte coupling. After a latency period, a subset of mice developed spontaneous recurrent seizures reminiscent of PTE in human patients with TBI. Seizing mice had larger areas of atypical astrocytes compared with nonseizing mice, suggesting that these atypical astrocytes might contribute to epileptogenesis after diffuse TBI. Traumatic brain injury is a leading cause of acquired epilepsies. Reactive astrocytes have long been associated with seizures and epilepsy in patients, particularly after focal/lesional brain injury. However, most TBIs also include nonfocal, diffuse injuries. Here, we showed that repetitive diffuse TBI is sufficient for the development of spontaneous recurrent seizures in a subset of mice. We identified an atypical response of astrocytes induced by diffuse TBI characterized by the rapid loss of homeostatic proteins and lack of astrocyte coupling while reactive astrocyte markers or glial scar formation was absent. Areas with atypical astrocytes were larger in animals that later developed seizures suggesting that this response may be one root cause of epileptogenesis after diffuse TBI.

中文翻译：

---

一击，一击-非常可触的一击：轻度TBI和癫痫的发展。

反复弥漫性轻度创伤性脑损伤可引起非典型星形胶质细胞反应和自发性反复发作Shandra O，Winemiller AR，Heithoff BP等。神经科学杂志。2019; 39（10）：1944-1963。doi：10.1523 / JNEUROSCI.1067-18.2018。Epub 2019一月21。PMID：30665946。局灶性外伤性脑损伤（TBI）会引起星形胶质增生，这是保护未受伤的大脑区域免受继发性损伤所必不可少的过程。然而，星形胶质细胞增生可导致星形胶质细胞稳态功能丧失，并可能导致合并症，例如创伤后癫痫（PTE）。形成疤痕的星形胶质细胞可将局灶性损伤与健康的大脑组织隔离开。这些胶质瘢痕与源自大脑皮层和海马体的癫痫有关。然而，绝大多数人类TBI还存在由导致组织剪切的加减速力引起的弥漫性脑损伤。所产生的弥漫性组织损伤可能与局灶性病变本质上不同，后者会触发神经胶质疤痕形成。在这里，我们在重复的轻度/震荡性闭合脑TBI模型中使用了这两种性别的小鼠，该模型仅诱发弥漫性损伤，以检验星形胶质细胞对弥漫性TBI有独特反应且弥漫性TBI足以引起PTE的假设。星形胶质细胞不形成疤痕，以胶质纤维酸性蛋白上调为特征的经典星形胶质细胞增生受到限制。令人惊讶的是，不相关的非典型反应性星形胶质细胞群的特征是神经胶质原纤维酸性蛋白表达缺乏，体内稳态蛋白快速持续的下调，和星形胶质细胞偶联受损。在潜伏期后，一部分小鼠在患有TBI的人类患者中出现了自发性反复发作，使人联想到PTE。与非扣押小鼠相比，扣押小鼠具有更大的非典型星形胶质细胞面积，这表明这些非典型星形胶质细胞可能在弥漫性TBI后有助于癫痫发生。颅脑外伤是获得性癫痫的主要原因。长期以来，反应性星形胶质细胞与患者的癫痫发作和癫痫病有关，尤其是在局灶性/病变性脑损伤后。但是，大多数TBI也包括非局灶性弥漫性损伤。在这里，我们表明，重复性弥漫性TBI足以使部分小鼠自发反复发作。我们确定了弥漫性TBI诱导的星形胶质细胞的非典型反应，其特征是稳态蛋白的快速丧失和星形胶质细胞的缺乏，而反应性星形胶质细胞标记物或神经胶质瘢痕的形成却不存在。动物中具有非典型星形胶质细胞的区域较大，随后会发作，提示这种反应可能是弥漫性TBI后癫痫发生的根本原因之一。