Cell cycle proteins preceded neuronal death after chronic cerebral hypoperfusion in rats

Abstract

Objectives: To explore the re-expression of cell cycle related proteins and delayed neuronal death after chronic cerebral hypoperfusion in rats and to investigate the relationship between aberrant expression of cell cycle proteins and apoptotic cell death.

Methods: Rat model of chronic cerebral hypoperfusion was established by permanent bilateral common carotid arteries occlusion (2VO) in the retired rats. The apoptotic cells were assessed by TUNEL method. The expression of cell cycle related proteins, i.e. CDK4 and cyclin B1, were detected by immunohistochemical staining and Western blotting. A cyclin-dependent kinases (CDKs) inhibitor, roscovitine, was intracerebroventricularly administered 1 day before 2VO insult. Spatial learning behavior was assessed by the Morris water maze 7, 14 and 21 days after the surgery.

Results: Aberrant expression of CDK4 and cyclin B1 became present 7 days after 2VO insult surgery and last for a long period. On the other hand, TUNEL positive cells appeared as early as 14 days after the surgery and peaked at day 21. Furthermore, roscovitine significantly improve behavioral deficit in the Morris water maze test 7 and 14 days after the surgery.

Conclusion: These findings indicated that aberrant expression of CDK4 and cyclin B1 takes place in the brain after chronic cerebral hypoperfusion in retired rat, and aberrant expression of cell cycle proteins preceded neuronal death in this model. Our data also suggest that the CDK inhibitor, roscovitine, has therapeutic potential for the treatment of dementia caused by chronic cerebral hypoperfusion.     

Doppler ultrasonographic measurement of blood flow velocities in major cerebral arteries of the rat using triplex mode

Abstract

Objective: In patients with subarachnoid hemorrhage, delayed cerebral ischemia caused by vasospasm of major cerebral arteries is an important factor of morbidity. While Doppler ultrasonographic monitoring of blood flow velocities is a routine bedside examination in these patients, the current rodent models of vasospasm do not include this technique. In this article, we present an extended craniectomy in rats, which allows for direct angle-corrected Doppler ultrasonographic examination of major cerebral vessels.

Methods: Ultrasonographic examination employs a triplex window displaying simultaneously B-mode, colour coded vessel rendering and Doppler-assessment of blood flow velocity. The animals receive anesthesia for the measurements, which are repeated several times a week.

Results: Mean flow velocities determined by 116 measurements in 16 animals are (cm/s): truncus cerebri anterius: 8.16, arteria pericallosa: 7.49, arteries (Aa.) cerebri anteriores: 7.76, Aa. carotides: 8.76, Aa. cerebri mediae: 8.55, Aa. cerebri posteriores: 5.27, artery (A.) basilaris: 5.90.

Discussion: We describe the direct intravital detection of blood flow velocities in major cerebral vessels of the rat. The technique allows for simultaneous visualization of intracranial structures, vessel diameters and cerebral blood flow velocities. Our ongoing research focuses on determining normal values in a larger population of animals and examining the feasibility of the technique regarding the rodent model of vasospasm.     

Neuroprotective effects of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), an antioxidant in middle cerebral artery occlusion induced focal cerebral ischemia in rats

Abstract

Objectives: In the present study, we have investigated the neuroprotective potential of 6hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), in middle cerebral artery occlusion (MCAO) induced focal cerebral ischemia.

Methods: Sprague–Dawley rats were subjected to 2 hours of MCAO followed by 22 or 70 hours of reperfusion. After reperfusion, rats were evaluated for neurological deficits and cerebral infarction. Brain malondialdehyde (MDA) level and in situ terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL) were also estimated.

Results: Focal cerebral ischemia produced a significant infarct volume and neurological scores as compared with sham-operated animals. Cerebral ischemia reperfusion injury was associated with an increase in lipid peroxidation in ipsilateral and contralateral hemisphere of brain along with an increase in TUNEL positive cells in ipsilateral hemisphere of brain sections indicating oxidative stress and DNA fragmentation, respectively. Trolox (10 and 30 mg/kg, i.p.) treatment significantly decreased neurological damage which was evident from the reduction in infarct volume and neurological score. Trolox (30 mg/kg) also attenuated oxidative stress and DNA fragmentation.

Discussion: Oxidative stress-induced neuronal damage is implicated in the pathophysiology of cerebral ischemia. Our study suggests that Trolox is a potent neuroprotective agent in focal cerebral ischemia and its neuroprotective effects may be attributed to the reduction of lipid peroxidation and DNA fragmentation.     

氧化应激在慢性缺血性脑白质损伤中的作用

目的 阐明氧化应激是否参与大鼠慢性脑缺血所致的脑白质损伤.方法 健康雄性Wistar大鼠按照完全随机数字表法分为假手术组,持久性双侧颈总动脉结扎3 d组、7 d组、3周组及6周组,每组6只.应用大鼠双侧颈总动脉结扎制备慢性脑缺血模型,检测大鼠脑白质内超氧化物歧化酶(SOD)活性、过氧化氢酶(CAT)活性、谷胱甘肽(GSH)含量以及脂质过氧化产物丙二醛(MDA)和4-羟基壬烯醛(4-HNE)加合物的变化.结果 与假手术组比较,慢性脑缺血大鼠脑白质内MDA含量在手术后3周明显增加,手术后6周进一步增高,差异有统计学意义(P<0.05).手术后3d至6周,慢性脑缺血大鼠脑白质内4-HNE蛋白加合物逐渐增高,与假手术组比较有差异有统计学意K(P<0.05).SOD活性在手术后3周和6周才明显降低,与假手术组比较差异有统计学意义(P<0.05).此外,慢性脑缺血大鼠脑白质内GSH含量在手术后7d即开始降低,而在手术后3周及6周则进一步下降,与假手术组比较差异有统计学意义(P<0.05).结论 慢性脑缺血导致大鼠脑白质氧化性损伤增加,抗氧化防御能力降低:氧化性损伤的增加和抗氧化防御能力的降低与慢性脑缺血所致的脑白质损伤密切相关.     

FK506 ameliorates the discrimination learning impairment due to preventing the rarefaction of white matter induced by chronic cerebral hypoperfusion in rats

We examined the effects of the immunosuppressant tacrolimus (FK506) on the discrimination learning impairment induced by chronic cerebral hypoperfusion in rats. Chronic cerebral hypoperfusion was prepared by permanent ligation of bilateral common carotid arteries for male Wistar rats aged 9 weeks. FK506 (0.05 mg/kg, s.c.) recovered the learning impairment and also prevented the rarefaction of white matter and striatal neuronal cell damage. Our findings suggest that FK506 ameliorates the learning impairment mainly due to preventing neuropathological alterations.     

绞股蓝总皂甙对慢性脑缺血性白质氧化性损伤的保护作用

目的 探讨绞股蓝总皂甙对慢性脑缺血大鼠脑白质氧化性损伤的保护作用以及对脑缺血大鼠认知功能的影响.方法 将57只成年雄性SD大鼠按随机数字表法分成假手术组(n=12)、模型组(n=15)、绞股蓝总皂甙200 mg组(n=15)、绞股蓝总皂甙400 mg组(n=15),后3组采用双侧颈总动脉结扎法制备慢性脑缺血模型,且在造模后3h分别将等量生理盐水,200 mg/kg、400mg/kg绞股蓝总皂甙溶液灌胃,1次/d,持续33 d.应用Morris水迷宫实验测试各组大鼠空间学习与记忆能力的改变,酶联免疫吸附法(ELISA)测定大鼠胼胝体、视束内超氧化物歧化酶(SOD)活性、丙二醛(MDA)含量,免疫组化染色用8-羟基脱氧鸟苷(8-OHdG)抗体测定中枢神经细胞的氧化损伤水平.结果 与模型组相比,绞股蓝总皂甙400 mg组大鼠的逃避潜伏期明显缩短及在原平台象限的游泳时间明显延长,差异有统计学意义(P＜0.05).与假手术组比较,模型组大鼠胼胝体及视束内MDA含量明显增加,SOD活性明显降低,差异有统计学意义(P＜0.05).与模型组相比,绞股蓝总皂甙400 mg组MDA含量明显降低,SOD活性明显升高,8-OHdG阳性细胞数明显减少,差异有统计学意义(P＜0.05).与模型组相比,绞股蓝总皂甙200 mg组SOD活性、MDA含量及8-OHdG阳性细胞数差异无统计学意义(P＞0.05).结论 绞股蓝总皂甙能有效改善慢性脑缺血大鼠脑白质氧化性损伤,提示其可能是一种有效的抗痴呆药物,但其作用的确切机制还有待进一步研究.     

Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: an immunohistochemical study

Activation of glial cells and white matter changes (rarefaction of the white matter) induced in the rat brain by permanent bilateral occlusion of the commom carotid arteries were immunohistochemically investigated up to 90 days. One day after ligation of the arteries, expression of the major histocompatibility complex (MHC) class I antigen in microglia increased in the white matter including the optic nerve, optic tract, corpus callosum, internal capsule, anterior commissure and traversing fiber bundles of the caudoputamen. After 3 days of occlusion, MHC class I antigen was still elevated and in addition MHC class II antigen and leukocyte common antigen were up-regulated in the microglia in these same regions. Astroglia, labeled with glial fibrillary acidic protein, increased in number in these regions after 7 days of occlusion. A few lymphocytes, labeled with CD4 or CD8 antibodies, were scattered in the neural parenchyma 1 h after occlusion. Activation of glial cells and infiltration of lymphocytes persisted after 90 days of occlusion in the white matter and the retinofugal pathway. However, cellular activation and infiltration in microinfarcts of the gray matter was less extensive and was substantially diminished 30 days after occlusion. The white matter changes were most intense in the optic nerve and optic tract, moderate in the medial part of the corpus callosum, internal capsule and anterior commissure, and slight in the fiber bundles of the caudoputamen. These results indicated that chronic cerebral hypoperfusion induced glial activation preferentially in the white matter. This activation seemed to be an early indicator of the subsequent changes in the white matter.     

慢性脑低灌注诱导神经细胞凋亡的实验研究

亡的时程变化。方法30只SD大鼠随机分为对照组(n=5)、模型不灌注组(n=5)、模型再灌注组动物按正常灌注压恢复后不同时间点分组(0h,n=5;12h,n=5;24h,n=5;72h,n=5)。模型组动物行右侧颈外静脉-颈总动脉端侧吻合,同时结扎左侧横窦引流静脉和双侧颈外动脉。术后3个月,阻断颈部动静脉分流造成模型组动物脑组织再灌注。流式细胞仪定量检测并比较各组动物右侧大脑中动脉区脑组织中神经细胞凋亡率,透射电镜观察神经元的超微结构。结果术后3个月,对照组和模型不灌注组动物脑组织中神经细胞凋亡率无明显差别。模型组动物再灌注即刻(0h)未见明显的神经细胞凋亡,再灌注12h神经细胞凋亡率开始明显增加,24h达高峰,72h降低。电镜证实神经细胞凋亡的存在。结论在慢性脑低灌注状态下,恢复正常灌注压可导致继发性神经细胞损害,可能与脑动静脉畸形切除术后迟发性神经功能障碍有关。     

Intensity of chronic cerebral hypoperfusion determines white/gray matter injury and cognitive/motor dysfunction in mice

We sought to establish a mouse model of subcortical ischemic vascular dementia (SIVD) that develops predominant white matter (WM) injury and cognitive dysfunction induced by chronic cerebral hypoperfusion. Adult C57Bl/6 male (n = 48) mice were subjected to bilateral common carotid artery stenosis with external microcoils (inner diameters: 0.16 mm, left; 0.18 mm, right). Mice were categorized according to left-side cerebral blood flow (CBF) value on day 6 into those with severe cerebral hypoperfusion (SCH; n = 16, < 30% of preoperative CBF baseline value) or moderate cerebral hypoperfusion (MCH; n = 21, 30-50% of preoperative value). Another 15 mice were sham operated. Neurological dysfunction was evaluated by Morris water maze, rotating rod, and open field tests. Histopathological examination was performed on day 35 after surgery. MCH animals showed persistent hyperlocomotion with reduced anxiety and spatial reference memory dysfunction. Rarefaction and small necrotic lesions were predominantly confined to the WM, with reactive astrocytosis, microglial infiltration, axonal loss, and myelin disruption, and these changes were dominant on the left side. SCH animals had persistent hyperlocomotion and motor dysfunction, and their ischemic lesions extended from the WM to the hippocampus and cortex. In MCH animals, myelin basic protein and neurofilament fiber densities in the WM were correlated with the time spent in the correct area in the water maze probe trials. Our MCH mouse model with the development of several types of neurological dysfunction with high reproducibility would be useful for investigating the pathomechanisms of WM injury in human SIVD.     

Axonal damage and demyelination in the white matter after chronic cerebral hypoperfusion in the rat

Cerebral white matter (WM) lesions are observed frequently in human ischemic cerebrovascular disease and have been thought to contribute to cognitive impairment. This type of lesion can be experimentally induced in rat brains under chronic cerebral hypoperfusion by the permanent occlusion of both common carotid arteries. However, it remains uncertain whether chronic ischemia can damage both the gray and white matter, and whether it can induce demyelination with or without axonal damage. Therefore, we examined axonal damage using immunohistochemistry for the amyloid beta/A4 precursor protein (APP), chromogranin A (CgA) and demyelination using immunohistochemistry for the encephalitogenic peptide (EP) in this model. Severe WM lesions such as vacuolation and the loss of nerve fibers appeared in the optic nerve and optic tract after 3 days of ligation, and less intense changes were observed in the corpus callosum, internal capsule, and fiber bundles of the caudoputamen after 7 days with Klüver-Barrera and Bielschowsky staining. These WM lesions persisted even after 30 days. The APP, CgA, and EP-immunopositive fibers increased in number from 1 to 30 days after the ligation in the following WM regions: the optic nerve, optic tract, corpus callosum, internal capsule, and fiber bundles of the caudoputamen. In contrast, only a few APP, CgA, or EP-immunopositive fibers were detected in the gray matter regions, including the cerebral cortex and hippocampus. These results indicate that the WM is more susceptible to chronic cerebral hypoperfusion than the gray matter, with an involvement of both axonal and myelin components. Furthermore, immunohistochemistry for APP, CgA, and EP is far superior to routine histological staining in sensitivity and may become a useful tool to investigate WM lesions caused by various pathoetiologies.     

Chronic cerebral hypoperfusion induced by right unilateral common carotid artery occlusion causes delayed white matter lesions and cognitive impairment in adult mice

Some lines of evidence have suggested that subcortical ischemic vascular dementia (SIVD) is a common form of vascular dementia (VaD), and that its pathological changes are the development of ischemic white matter (WM) lesions under chronic hypoperfusion and lacunes. Here, we have developed a novel mouse model of VaD with WM lesions, which was induced by right unilateral common carotid artery occlusion (rUCCAO). The mice subjected to rUCCAO exhibited chronic cerebral hypoperfusion in the cerebral hemisphere ipsilateral to rUCCAO monitored using a laser-Doppler flow meter (p<0.01), and significant WM damage in the corpus callosum (p<0.05) and deficits in object recognition test correlated with the damage of frontal-subcortical circuits (p<0.01). However, no differences in spontaneous alternation or spontaneous motor activity were observed. Furthermore, the levels of pro-inflammatory cytokines, such as interleukin-1beta (IL-1beta) and interleukin-6 (IL-6), significantly increased (p<0.01), and those of anti-inflammatory cytokines, such as interleukin-4 (IL-4) and interleukin-10 (IL-10), significantly decreased in the ischemic brain (p<0.05). These results suggest that this model is a useful tool for investigating the associations among inflammatory reactions, cognitive impairment, and WM damage, which may help elucidating the pathomechanism of VaD, particularly SIVD.     

慢性间断缺氧对老年期大鼠脑白质的影响

目的研究慢性间断缺氧对老年期大鼠脑白质的影响。方法建立老年期SD大鼠慢性间断缺氧模型,免疫组化检测大鼠脑室旁白质髓鞘碱性蛋白（myelin basic protein,MBP）、神经微丝H＋L（neutofilament—H＋L,NF-H＋L）、胶质纤维酸性蛋白（glial fibrillary acidic protein,GFAP）表达并行图像分析;电镜下观察大鼠脑内髓鞘、轴突的超微结构。结果慢性间断缺氧可使老年期大鼠脑白质MBP、NF-H＋L表达减少及GFAP表达增加（P均〈0．05）,MBP与NF-H＋L呈高度正相关（R^2=0．908,P〈0．01）。电镜观察与空白对照组比较,缺氧组大鼠脑内可见较多的髓鞘脱失、轴突受损。结论慢性间断缺氧可对老年期大鼠脑白质产生不良影响,表现为髓鞘脱失、轴突变性以及神经胶质增生。     

慢性脑缺血老龄大鼠海马中突触素的表达特征

目的 研究老龄大鼠慢性脑缺血后大脑海马中突触素表达特征.方法 应用免疫组化染色技术检测大鼠脑海马中CA1区、CA3区和齿状回中突触素的表达.结果 缺血组海马CA1区、CA3区和齿状回三处突触素灰度值均低于对照组,差异有统计学意义(P<0.05.结论 老龄大鼠海马结构内CA1区、CA3区及齿状回内突触素和NR2B的表达明显减少.     

老龄大鼠慢性脑灌注不足脑内白细胞和T细胞的入侵

目的 探讨白细胞和Ｔ细胞在慢性脑灌注不足脑损害中的活动。方法 ７０只老龄Ｗｉｓｔａｒ大鼠持久性双侧颈总动脉结扎（２ＶＯ）,其中１２只接受环孢霉素Ａ（ＣｓＡ）治疗。免疫组化法检测白细胞和Ｔ细胞。实现研究为持久性２Ｖ０１～４月。结果 大鼠慢性脑灌注不足造成了明显的脑损害与白细胞和Ｔ细胞的入侵。１～４月,白细胞在皮层、白质和海马的活动均减少,而Ｔ细胞的活动在皮层下白质增多,在皮层和海马减少。同时脑损害加重。ＣｓＡ治疗后白细胞和Ｔ细胞的活动明显减弱,脑损害减轻。结论 慢性脑灌注不足的病理损害,尤其白质损害中,Ｔ细胞伴有重要作用,白细胞仅起次要作用。ＣｓＡ能抑制白细胞和Ｔ细胞的活动,从而防治了脑损害。     

丁基苯酞对老龄大鼠慢性脑缺血后HO-1和VEGF表达的影响

目的 研究丁基苯酞(Dlbutylphthalide ,NBP)对大鼠慢性脑缺血后大脑皮层和海马中VEGF和HO-1表达的影响.方法 用免疫组织化学SP法在光镜下观察各组皮层和海马VEGF和HO-1的表达.结果 B组皮质和海马VEGF和HO-1表达与A组相比明显增多.C组、D组和B组相比VEGF和HO-1表达明显增多,D组和C组相比VEGF和HO-1表达明显增多,差异有统计学意义.结论 丁基苯酞对慢性脑缺血的保护作用可能通过上调脑组织中的VEGF和HO-1的表达而实现.     

慢性脑缺血老龄大鼠海马NMDA受体亚单位NR2B表达的特征

目的研究老龄大鼠慢性脑缺血后大脑海马中NR2B表达特征。方法应用免疫组化染色技术检测大鼠脑海马中CA1、CA3区和齿状回中NR2B的表达。结果缺血组海马CA1、CA3区和齿状回三处NR2B灰度值均低于对照组,差异具有统计学意义(P<0.05)。结论老龄大鼠海马结构内CA1、CA3区及齿状回内NR2B的表达明显减少。     

丰富环境对慢性脑低灌注大鼠甲状腺激素及其受体的影响

目的 观察慢性脑低灌注大鼠学习记忆能力和甲状腺激素及其受体的变化,以及丰富环境干预的影响.方法 采用随机数字表法将48只大鼠分为4组,每组12只:假手术+标准环境( sham+ SE)组、双血管结扎手术+标准环境(2-VO+ SE)组、假手术+丰富环境(sham+ EE)组和双血管结扎手术+丰富环境( 2-VO+ EE)组.采用Morris水迷宫、放射免疫法、免疫组织化学染色和Western blot方法分别检测大鼠的学习记忆能力、血清甲状腺激素水平以及海马甲状腺激素受体(thyroid hormone receptor α1,TRα1)水平.结果 Morris水迷宫结果显示2-VO+ SE组大鼠在训练的第2、4和5天找到平台的时间显著多于sham+ SE组(t=2.67、2.67和3.18,P＜0.05、0.05和0.01),而2-VO+ EE组大鼠在第4和5天找到平台的时间显著少于2-VO+ SE组(t=4.08和3.55,均P＜0.01);2-VO+ SE组大鼠在目标象限花费的时间显著低于sham+ SE组(t=3.33,P＜0.05),而2-VO+ EE组大鼠在目标象限花费的时间显著多于2-VO+ SE组(t=4.46,P＜0.01).放射免疫检测结果显示,与sham+ SE组(0.60±0.15)比较,2-VO+ SE组(0.40±0.04)大鼠血清三碘甲状腺原氨酸(T3)的水平降低;而与2-VO+ SE组比较,2-VO+ EE组(0.66±0.08)大鼠血清T3的水平明显增加(t =3.62,P＜0.01).免疫组织化学结果显示,与sham+ SE组比较,2-VO+ SE组大鼠海马CA1和DG区TRα1积分吸光度值明显降低(t=3.18、3.20,均P＜0.05);而与2-VO+ SE组比较,2-VO+ EE 组大鼠海马CA1和DG区TRα1积分吸光度值明显增强(t=3.93、4.12,均P＜0.01).Western blot结果显示,与sham+ SE组比较,2-VO+ SE组大鼠海马TRα1定量分析相对吸光度值明显下降(t=4.35,P＜0.05);而与2-VO+ SE组比较,2-VO+ EE组大鼠海马TRα1定量分析相对吸光度值明显增强(t=6.20,P＜0.01).结论 慢性脑低灌注可以损害海马相关的学习记忆,而丰富环境干预可以改善慢性脑低灌注引起的学习记忆损害;血清甲状腺激素T3和海马TRα1可能参与丰富环境对认知功能损害的改善作用.     

丁基苯酞对慢性脑缺血老龄大鼠海马中NMDA受体亚单位NR2B及突触素表达的影响

目的 观察丁基苯酞对慢性脑缺血老龄大鼠海马中N-甲基-D-天门冬氨酸受体2B亚单位(NR2B)及突触素表达的影响.方法 采用免疫组化方法观察丁基苯酞对慢性脑缺血老龄大鼠海马中NR2B及突触素表达的影响.结果 B组与A组比较,海马CA1区、CA3区及齿状回NR2B及突触素的表达明显减少(P＜0.05),C、D组大鼠海马各区NR2B及突触素的表达与单纯缺血组比较均不同程度增加(P＜0.05);D组与C组比较,NR2B及突触素的表达增加更明显(P＜0.05).结论 慢性缺血3个月后,大鼠海马CA1区、CA3区及齿状回中NR2B 及突触素的表达明显减少,而丁基苯酞能改善这种缺血改变,增加NR2B 及突触素的表达.     

Short‐ and long‐term functional plasticity of white matter induced by oligodendrocyte depolarization in the hippocampus

Plastic changes in white matter have received considerable attention in relation to normal cognitive function and learning. Oligodendrocytes and myelin, which constitute the white matter in the central nervous system, can respond to neuronal activity with prolonged depolarization of membrane potential and/or an increase in the intracellular Ca²⁺ concentration. Depolarization of oligodendrocytes increases the conduction velocity of an action potential along axons myelinated by the depolarized oligodendrocytes, indicating that white matter shows functional plasticity, as well as structural plasticity. However, the properties and mechanism of oligodendrocyte depolarization‐induced functional plastic changes in white matter are largely unknown. Here, we investigated the functional plasticity of white matter in the hippocampus using mice with oligodendrocytes expressing channelrhodopsin‐2. Using extracellular recordings of compound action potentials at the alveus of the hippocampus, we demonstrated that light‐evoked depolarization of oligodendrocytes induced early‐ and late‐onset facilitation of axonal conduction that was dependent on the magnitude of oligodendrocyte depolarization; the former lasted for approximately 10 min, whereas the latter continued for up to 3 h. Using whole‐cell recordings from CA1 pyramidal cells and recordings of antidromic action potentials, we found that the early‐onset short‐lasting component included the synchronization of action potentials. Moreover, pharmacological analysis demonstrated that the activation of Ba²⁺‐sensitive K⁺ channels was involved in early‐ and late‐onset facilitation, whereas 4‐aminopyridine‐sensitive K⁺ channels were only involved in the early‐onset component. These results demonstrate that oligodendrocyte depolarization induces short‐ and long‐term functional plastic changes in the white matter of the hippocampus and plays active roles in brain functions. GLIA 2014;62:1299–1312