黑木耳多糖对抗大鼠慢性缺血性脑损伤

目的:观察黑木耳多糖(AAP)对大鼠慢性脑缺血损伤的保护作用,并探讨其相关机制。方法:雄性成年SD大鼠右侧永久性大脑中动脉栓塞(MCAO),建立慢性脑缺血模型,缺血后每天分别给予不同浓度的AAP灌胃4周。银杏叶提取物作为阳性对照。4周后采用Morris水迷宫检测大鼠学习记忆能力。取脑做冰冻切片进行Nissl染色,观察存活神经元数量,并测定脑组织丙二醛(MDA)水平和超氧化物歧化酶(SOD)活性。结果:AAP能明显改善脑缺血大鼠的学习记忆能力,增加海马神经元的存活数量,并且能够使脑组织长期MCAO诱导的MDA生成减少,使SOD活性显著升高。高剂量AAP(200mg/kg)的作用和银杏叶提取物相比更明显。结论:AAP明显减轻大鼠慢性脑缺血损伤,其作用与其对抗过氧化应激有关。     

慢性强迫游泳应激抑郁模型大鼠行为学及海马Ca2+/钙调蛋白依赖性激酶Ⅱ的变化

目的 探讨慢性强迫游泳应激(CFSS)模型大鼠行为学的改变和海马神经元Ca²⁺/钙调蛋白依赖性激酶Ⅱ（CaMKⅡ）的表达变化。 方法 成年健康雄性Wistar大鼠60只,随机分为对照组（30只）和慢性强迫游泳应激组（30只）。慢性强迫游泳组强迫游泳4周,制备慢性强迫游泳应激模型;糖水偏好实验、开场实验和Morris水迷宫检测大鼠行为学改变;荧光探针标记法测定海马神经元内Ca²⁺浓度;胶体金免疫电镜、免疫印迹和RT-PCR检测CaMKⅡ的表达变化。 结果 慢性强迫游泳应激组糖水消耗量和糖水偏好百分比分别为4.114±0.644和86.610±4.450,对照组为8.157±1.105和94.930±2.893,差异有统计学意义（P<0.01）;开场实验中慢性强迫游泳应激组和对照组的直立次数分别为1.75±0.96和6.00±0.82,差异有统计学意义（P<0.05）;水迷宫实验逃避潜伏期分别为（20.762±3.236）s和（5.632±1.065）s,差异有统计学意义（P<0.01）;海马神经元内游离Ca 2+浓度分别为（498.94±40.45）nmol/L和（288.91±32.42）nmol/L,差异有统计学意义（P<0.01）;CaMKⅡ蛋白和mRNA相对表达水平均高于对照组（P<0.01）。 结论 海马Ca²⁺及CaMKⅡ的表达上调,可能是抑郁模型大鼠情感行为异常的病理生理基础之一。     

慢性强迫游泳应激抑郁模型大鼠行为学及海马Ca~(2+)/钙调蛋白依赖性激酶Ⅱ的变化

目的 探讨慢性强迫游泳应激(CFSS)模型大鼠行为学的改变和海马神经元Ca~(2+)/钙调蛋白依赖性激酶Ⅱ(CaMKⅡ)的表达变化. 方法 成年健康雄性Wistar大鼠60只,随机分为对照组(30只)和慢性强迫游泳应激组(30只).慢性强迫游泳组强迫游泳4周,制备慢性强迫游泳应激模型;糖水偏好实验、开场实验和Morris水迷宫检测大鼠行为学改变;荧光探针标记法测定海马神经元内Ca~(2+)浓度;胶体金免疫电镜、免疫印迹和RT-PCR检测CaMKⅡ的表达变化. 结果 慢性强迫游泳应激组糖水消耗量和糖水偏好百分比分别为4.114±0.644和86.610±4.450,对照组为8.157±1.105和94.930±2.893,差异有统计学意义(P<0.01);开场实验中慢性强迫游泳应激组和对照组的直立次数分别为1.75±0.96和6.00±0.82,差异有统计学意义(P<0.05);水迷宫实验逃避潜伏期分别为(20.762±3.236)s和(5.632±1.065)s,差异有统计学意义(P<0.01);海马神经元内游离Ca~(2+)浓度分别为(498.94±40.45)nmol/L和(288.91±32.42)nmol/L,差异有统计学意义(P<0.01);CaMKⅡ蛋白和mRNA相对表达水平均高于对照组(P<0.01). 结论 海马Ca~(2+)及CaMKⅡ的表达上调,可能是抑郁模型大鼠情感行为异常的病理生理基础之一.     

Duration-dependent effects of the bite-raised condition on hippocampal function in SAMP8 mice

We evaluated the effect of the duration of occlusal disharmony induced chronic stress on hippocampal function by examining spatial memory in the Morris water maze and on the number of hippocampal neurons in aged senescence-accelerated prone (SAMP8) mice. The bite of SAMP8 mice was raised 0.1 mm using dental adhesive. Groups of mice were tested in the Morris water maze 8, 11, or 22 d after raising the bite. The results indicated that the longer the duration of the bite-raised condition, the greater the impairment in spatial learning ability and the greater the decrease in the number of neurons in the hippocampal CA3 subfield. Thus, behavioral and morphologic deficits induced by the bite-raised condition in aged SAMP8 mice are influenced by the duration of the occlusal disharmony.     

Prenatal exposure to lipopolysaccharide results in cognitive deficits in age-increasing offspring rats

Studies have suggested that maternal infection/inflammation maybe a major risk factor for neurodevelopmental brain damage. In the present study, we evaluated the effects of prenatal exposure to a low level of inflammatory stimulation lipopolysaccharide (LPS) repeatedly on spatial learning and memory performances in rat offspring's lifetime. Sixteen pregnant Sprague–Dawley rats were randomly divided into two groups. The rats in the LPS group were treated i.p. with LPS (0.79 mg/kg) at gestation day 8, 10 and 12; meanwhile the rats in the control group were treated with saline. After delivery, the rat offspring at 3- (young), 10- (adult) and 20-mon-old (aged) were allocated. Spatial learning and memory abilities were tested by Morris water maze. The structure of hippocampal CA1 region was observed by light microscopy. The expression of synaptophysin (SYP) and glial fibrillary acidic protein (GFAP) in hippocampal CA1 region were measured by immunohistochemistry. Results showed that the rat offspring of LPS group needed longer escape latency and path-length in the Morris water maze and presented a significant neuron loss, decreased expression of SYP, increased expression of GFAP in CA1 region in histological studies. All these changes were more significant with the age increasing. These findings support the hypothesis that maternal systemic inflammation may alter the state of astrocytes in rat offspring for a long time, the alteration may affect neurons and synapse development in neural system, increase the neurons' vulnerability to environment especially as the age increasing, at last result in distinct learning and memory impairment.     

Nerve growth factor improves spatial learning and restores hippocampal cholinergic fibers in rats withdrawn from chronic treatment with ethanol

The cholinergic septohippocampal pathway has long been known to be important for learning and memory. Prolonged intake of ethanol causes enduring memory deficits, which are paralleled by partial depletion of hippocampal cholinergic afferents. We hypothesized that exogenous supply of nerve growth factor (NGF), known to serve as a trophic substance for septal cholinergic neurons, can revert the ethanol-induced changes in the septohippocampal cholinergic system. Adult rats were given a 20% ethanol solution as their only source of fluid for 6 months. During the first 4 weeks after the animals were withdrawn from ethanol, they were intraventricularly infused with either NGF or vehicle alone via implanted osmotic minipumps. The vehicle-infused withdrawn animals showed impaired performance on a spatial reference memory version of the Morris water maze task, both during the task acquisition and on the retention test. In contrast, NGF-treated withdrawn rats were able to learn the task as well as controls, and significantly outperformed the vehicle-infused withdrawn rats. The histological analysis revealed that, in the latter group, the length density of fibers immunoreactive to choline acetyltransferase was reduced relative to control values by approximately 25%, as measured in the dentate gyrus and regio superior of the hippocampal formation. However, in NGF-treated withdrawn rats, the length density of these fibers was identical to that of control rats. These data provide support to the notion that NGF is capable of ameliorating memory deficits and restoring septohippocampal cholinergic projections following chronic treatment with ethanol. Electronic Publication     

Red wine antioxidants protect hippocampal neurons against ethanol-induced damage: a biochemical, morphological and behavioral study

Chronic ethanol consumption increases oxidative stress, which accounts for the striking neurological changes seen in this condition. Notwithstanding, there is well-documented evidence that polyphenols, present in grape skin and seeds, exhibit a strong antioxidant activity. As red wine is rich in polyphenols, the aim of the present work was to evaluate their putative protective effects on the hippocampal formation by applying biochemical, morphological and behavioral approaches. Six-month old male Wistar rats were fed with red wine (ethanol content adjusted to 20%) and the results were compared with those from ethanol-treated (20%) rats and pair-fed controls. Biochemical markers of oxidative stress (lipid peroxidation, glutathione levels and antioxidant enzyme activities) were assessed on hippocampal homogenates. Lipofuscin pigment, an end product of lipid peroxidation, was quantified in hippocampal cornu ammonis 1 and 3 (CA1 and CA3) pyramidal neurons using stereological methods. All animals were behaviorally tested on the Morris water maze in order to assess their spatial learning and memory skills. In red wine-treated rats, lipid peroxidation was the lowest while presenting the highest levels of reduced glutathione and an induction of antioxidant enzyme activities. Morphological findings revealed that, contrary to ethanol, red wine did not increase lipofuscin deposition in CA1 and CA3 pyramidal neurons. Besides, red wine-treated animals learned the water maze task at a higher rate than ethanol group and had better performance scores by the end of the training period and on a probe trial. Actually, no significant differences were found between pair-fed controls and red wine-treated rats in morphological and behavioral data. Thus, our findings demonstrate that chronic consumption of red wine, unlike the ethanol solution alone, does not lead to a decline in hippocampal-dependent spatial memory. This may be due to the ability of red wine polyphenols to improve the antioxidant status in the brain and to prevent free radical-induced neuronal damage.     

KA诱发癫痫反复发作损伤大鼠空间学习记忆及中脑多巴胺能神经元

目的探讨颞叶癫痫反复发作(Spontaneous recurrent se izure,SRS)对大鼠空间学习记忆影响及中脑内多巴胺能神经元变化。方法以红藻氨酸(kain ic ac id,KA)制备颞叶癫痫大鼠模型,以是否出现SRS为标准将KA大鼠分为伴有反复发作和不伴有反复发作组,盐水为对照组。分别进行水迷宫行为测试,评价其学习记忆能力;并用酪氨酸羟化酶(Tyrosine hydroxylase,TH)免疫组化方法来观察各组大鼠中脑内多巴胺能神经元变化。结果KA处理后,按照Rac ine描述标准,KA组动物发作全部达到4~5级。KA后3周大鼠19只出现SRS,16只未见SRS;Morris水迷宫发现,在5 d的空间学习记忆测试中,反复发作KA大鼠的寻找潜伏期明显长于不伴有SRS的KA大鼠和盐水对照组(P<0.01),而不伴有SRS组与盐水对照组没有明显差别;伴有SRS的KA组大鼠总共穿过平台次数显著少于不伴有SRS的KA组大鼠和盐水对照组(P<0.01)。TH免疫组织化学结果发现与不伴有SRS的KA大鼠和盐水对照组比较,伴有SRS的KA大鼠在腹侧被盖的多巴胺能神经元大量脱失(P<0.01)。结论KA大鼠癫痫反复发作可能与空间学习记忆障碍和在腹侧被盖多巴胺能神经元大量脱失相关。     

β淀粉样蛋白对大鼠学习记忆功能及tau蛋白异常磷酸化的影响

为了探讨β淀粉样蛋白对大鼠学习记忆功能和tau蛋白异常磷酸化的影响,本文在海马注射Aβ25-35建立阿尔茨海黙病(AD)大鼠模型的基础上,通过行为学检测、HE染色、免疫组化和免疫蛋白印迹技术对动物的学习能力、组织的病理改变和tau(pS202)、tau(pT231)和tau-5的表达情况进行了分析。在行为学检测中,Aβ注射组大鼠在穿梭箱实验中的主动回避次数和被动回避次数减少,失败次数增多,而在Morris水迷宫测试中的逃避潜伏期和游泳距离延长。HE染色显示Aβ注射组大鼠海马CA1、CA3、齿状回的神经细胞数目减少;而免疫组化和免疫印迹结果显示注射组tau(pS202)阳性细胞明显增加,tau(pS202)、tau(pT231)和tau-5蛋白表达增加。以上结果提示海马内注射Aβ25-35可引起大鼠学习记忆功能下降,可能与神经细胞减少,tau蛋白异常磷酸化增多有关。     

Changes in hippocampal synapses and learning-memory abilities in age-increasing rats and effects of tetrahydroxystilbene glucoside in aged rats

The aim of the present study is to investigate the changes in hippocampal synapses and their relation with learning-memory abilities at different ages, and evaluate the effects of 2,3,5,4'-tetrahydroxystilbene-2-O-beta-d-glucoside (TSG), which is one of the major components of a traditional Chinese herb Polygonum multiflorum, on brain aging. Sprague-Dawley rats at the age of 1, 3, 6, 18 and 24 months were used. TSG at doses of 30 and 60 mg/kg/day was intragastrically administered to 21-month-old rats for 3 months, respectively. Learning-memory abilities were determined by Morris water maze and passageway water maze tests. The ultrastructure of synapses in the hippocampal CA1 region was observed by electronic microscopy. The expression of synaptophysin (SYP) in whole hippocampus was measured by using immunohistochemistry. Compared with rats at 6 months of age, both the 1-month-old rats and 24-month-old rats showed longer escape latency and swimming distance in the Morris water maze test, while more errors were detected in the passageway water maze test, with a smaller number of synapses and synaptic vesicles and less expression of SYP in the hippocampus. Treatment with high-dose TSG in rats at 24 months of age had significant improvement in the learning-memory abilities in the water maze tests associated with an increase in the number of synapses and synaptic vesicles, and an elevation of expression of SYP in the hippocampus. In conclusion, hippocampal synapses count and synaptophysin expression decreased in aged rats, which may be one of the mechanisms involved in learning-memory deficit. TSG reversed the above changes in aged rats, suggesting that TSG may be beneficial for the treatment of Alzheimer disease or cognitive impairment in old people.     

Involvement of cyclin-dependent kinase 5/p35(nck5a) in the synaptic reorganization of rat hippocampus during kindling progression

To test the hypothesis that a complex of cyclin-dependent kinase 5 (Cdk5) and p35(nck5a) plays an important role in sprouting in the kindling rat hippocampus, we studied the changes in kinase activity, expression level and subcellular localization during kindling progression. The kinase activity in kindling rats was significantly higher than that in normal rats. The changes in kinase activity coincided with those of the p35(nck5a) expression in kindling rats. In contrast, the expression of Cdk5 was constant at all stages of kindling. Subcellular localization of Cdk5, however, changed markedly in the hippocampal neurons during kindling progression. Cdk5 translocated from axon to soma when the kinase activity was high. The phosphorylation level of tau protein was in good agreement with the Cdk5 kinase activity. In contrast, MAP kinase activity was not correlated with tau phosphorylation during kindling progression. These findings suggest that Cdk5/p35(nck5a) plays an important role in synaptic reorganization, and the translocation of Cdk5 to soma from axons is a crucial regulatory mechanism of kinase activity.     

Learning deficits after experimental subarachnoid hemorrhage in rats

About 50% of subarachnoid hemorrhage (SAH) survivors have cognitive or neurobehavioral dysfunction. The mechanisms are not known. This study characterized behavioral deficits in a rat SAH model, and correlated these changes with histological alterations. SAH was induced by injection of 0.3 ml blood into the prechiasmatic cistern. Cognitive and memory changes were investigated in the Morris water maze. Neuronal cell death was evaluated by fluoro-jade and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Vasospasm was assessed on cross-sections of middle and anterior cerebral arteries. Microthromboemboli were quantified by fibrinogen staining. Escape latency and swimming distance were significantly increased in rats with SAH as compared to controls (P<0.05–0.001). SAH rats tended to do poorly on accuracy in spatial and working memory tests. SAH rats had a significantly higher number of fluoro-jade and TUNEL positive neurons in CA1 and CA3 of the hippocampus, cerebral cortex and Purkinje cells in the cerebellum (P<0.05–0.001). The number of microthromboemboli in the cortex and cerebellum were significantly higher after SAH than in controls (P<0.05–0.001). Cognitive deficits were induced by SAH in rats. There was a significant increase in apoptotic neurons in all regions of brain examined. However, cell death in the hippocampus was not sufficient to cause the neurobehavioral deficits observed in the Morris water maze. This suggests that other factors such as dysfunction of neurotransmission or plasticity in hippocampal pathways might contribute to the impairments.     

The effect of ganglioside GQ1b on the NMDA receptor signaling pathway in H19-7 cells and rat hippocampus

Gangliosides, sialic acid-containing glycosphingolipids, are related to various synaptic functions in the rat brain. Previously, we investigated the behavioral effects of the ganglioside GQ1b on learning and memory using the Y-maze and Morris water maze test. GQ1b-treated rats showed highly increased memory performance on the Y-maze and the Morris water maze test. In this study, we determined the role of GQ1b on the activation of the N-methyl-d-aspartate (NMDA) receptor signaling pathway in H19-7 rat hippocampal cells and the hippocampus of rats. After 12 h of treatment with GQ1b, the expression levels of NMDA receptor subunit 2A and 2B were increased in H19-7 cells and the hippocampus of rats. In addition, treatment of GQ1b increased the tyrosine phosphorylation of NR2B that may enhance NMDA receptor synaptic activation and enhancement of NMDA receptors. Also, following GQ1b treatment, the phosphorylation of extracellular signal-regulated kinases (ERK1/2) and protein kinase A, a cAMP activated protein kinase (PKA) increased in H19-7 cells and the hippocampus of rats. These increases resulted in an increase in the phosphorylation of cAMP response element binding protein (CREB). These results suggest that GQ1b might facilitate the activation of the NMDA receptor signaling pathway in the hippocampus of rats, an effect which is dependent on ERK1/2, PKA and CREB phosphorylation. Also, these data support our previous result that GQ1b improves the learning and memory of rats.     

Working memory training decreases hippocampal neurogenesis

The relationship between adult hippocampal neurogenesis and cognition appears more complex than suggested by early reports. We aimed to determine if the duration and task demands of spatial memory training differentially affect hippocampal neurogenesis. Adult male rats were trained in the Morris water maze in a reference memory task for 4 days, or alternatively working memory for either 4 or 14 days. Four days of maze training did not impact neurogenesis regardless of whether reference or working memory paradigms were used. Interestingly, 2 weeks of working memory training using a hidden platform resulted in fewer newborn hippocampal neurons compared with controls that received either cue training or no maze exposure. Stress is a well-established negative regulator of hippocampal neurogenesis. We found that maze training in general, and a working memory task in particular, increased levels of circulating corticosterone after 4 days of training. Our study indicates that working memory training over a prolonged period of time reduces neurogenesis, and this reduction may partially be mediated by increased stress.     

亚甲蓝对APP/PS1转基因小鼠学习记忆及海马结构内GFAP表达的影响

目的:观察亚甲蓝对APP/PS1转基因小鼠学习记忆及胶质纤维酸性蛋白(Glial fibrillary acidic pro-tein,GFAP)在海马结构表达变化的影响。方法:20只3月龄APP/PS1小鼠,随机分2组,每组10只,对照组:自由饮水;治疗组:根据小鼠饮水量将亚甲蓝加入日常饮水中(25 mg/kg/d)连用4个月至7月龄。水迷宫测试观察其行为学的改变,免疫组化、Western Blot和TUNEL染色法观察GFAP在海马结构的表达及神经元的凋亡情况。结果:水迷宫测试结果显示亚甲蓝喂养组APP/PS1转基因小鼠第2～4 d的平均潜伏期显著低于对照组小鼠的潜伏期,说明治疗组与对照组相比在7个月时出现明显差异(P<0.05);免疫组化和Western结果显示治疗组海马结构内的GFAP在APP/PS1转基因小鼠的表达下调(P<0.05)。TUNEL染色法显示治疗组海马CA1、CA3区和齿状回TUNEL阳性细胞数较对照组明显减少(P<0.05)。结论:亚甲蓝能够下调APP/PS1小鼠海马结构内GFAP蛋白的表达,并通过抑制海马结构神经元的凋亡,提高APP/PS1小鼠的认知能力。     

慢性复合应激增强大鼠海马Doublecortin的表达

目的 探讨慢性复合应激性学习记忆增强大鼠海马齿状回(DG)新生神经元数量变化以及Doublecortin(DCX)在海马组织中表达的变化及其意义.方法 成年雄性大鼠随机分为复合应激组和正常对照组.复合应激组动物每天交替暴露于复合应激原中达6周.实验结束后,所有动物分别进行3d的Morris水迷宫测试,记录其学习和记忆成绩.运用免疫细胞化学方法观察海马DG新生神经元数量的变化,同时运用Western blotting和RT-PCR技术分别检测DCX在海马的表达及其mRNA水平的变化.结果 与对照组相比,复合应激组动物的学习与记忆成绩优于对照组(P＜0.05);其海马DG新生神经元数明显增多(P＜0.05);海马DCX蛋白的表达明显增加(P＜0.05);海马DCX mRNA水平明显上调(P＜0.05).结论 慢性复合应激致大鼠的学习与记忆能力增强,海马DG内DCX阳性细胞数增多,提示新生神经元数量增加是导致大鼠学习记忆能力增强的原因之一.     

Orexin-A (hypocretin-1) impairs Morris water maze performance and CA1-Schaffer collateral long-term potentiation in rats

Glucose-sensitive neurons in the lateral hypothalamic area produce orexin-A (hypocretin-1) and orexin-B (hypocretin-2) and send their axons to the hippocampus, which predominantly expresses orexin receptor 1 showing a higher sensitivity to orexin-A. The purpose of the present study was to assess the effects of orexin-A on the performance of Wistar rats during the Morris water maze test and then to determine the effects of orexin-A on both the long-term potentiation and long-term depression in Schaffer collateral/commissural-CA1 synapses in hippocampal slices. The results of the Morris water maze test show that 1.0 and 10 nmol of orexin-A, when administered intracerebroventricularly, retarded spatial learning. A probe test examined after training of water maze task also showed an impairment in spatial memory. The results of an electrophysiological study using hippocampal slices demonstrated that 1.0 to 30 nM of orexin-A applied to the perfusate produces a dose-dependent and time dependent suppression of the long-term potentiation. In addition, the long-term depression was not affected by orexin-A. The results of a paired-pulse facilitation experiment indicated that the effects of orexin-A were post-synaptic and not due to presynaptic transmitter release. These results show that orexin-A impairs spatial performance and these impairments can be attributed to a suppression of long-term potentiation in the Schaffer collateral-CA1 hippocampal synapses.     

Young hippocampal neurons are critical for recent and remote spatial memory in adult mice

New granule cells are continuously generated throughout adulthood in the mammalian hippocampus. These newly generated neurons become functionally integrated into existing hippocampal neuronal networks, such as those that support retrieval of remote spatial memory. Here, we sought to examine whether the contribution of newly born neurons depends on the type of learning and memory task in mice. To do so, we reduced neurogenesis with a cytostatic agent and examined whether depletion of young hippocampal neurons affects learning and/or memory in two hippocampal-dependent tasks (spatial navigation in the Morris water maze and object location test) and two hippocampal-independent tasks (cued navigation in the Morris water maze and novel object recognition). Double immunohistofluorescent labeling of the birth dating marker 5-bromo-2'deoxyuridine (BrdU) together with NeuN, a neuron specific marker, was employed to quantify reduction of hippocampal neurogenesis. We found that depletion of young adult-generated neurons alters recent and remote memory in spatial tasks but spares non-spatial tasks. Our findings provide additional evidence that generation of new cells in the adult brain is crucial for hippocampal-dependent cognitive functions.     

Lithium-pilocarpine-induced status epilepticus in immature rats result in long-term deficits in spatial learning and hippocampal cell loss

Rat pups age of 14 postnatal day (P14) were subjected to lithium-pilocarpine (Li-PC) model of status epilepticus (SE). Control rats (n=6) were given an equivalent volume of saline intraperitoneally. Behavioral testing began on P60 including the Morris water maze, the radial arm maze, and the rotarod test. Brain were then analyzed with cresyl violet stain for histological lesions and evaluated for mossy fiber sprouting with the Timm stain. We observed spatial memory deficits both in the Morris water maze and radial arm maze in Li-PC-treated rat. There was no motor impairment in Li-PC-treated rat by the rotarod test. Two of six Li-PC-treated rats showed cell loss in hippocampal CA1 subfield. The Timm staining pattern was similar in both control and Li-PC-treated rats. Result of this study suggests that Li-PC-induced SE in immature rats cause long-term cognitive deficit and permanent cell loss in hippocampal CA1, but spare motor impairment.     

Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors

CA1 pyramidal neurons degenerate after transient forebrain ischemia, whereas neurons in other regions of the hippocampus remain intact. Here we show that in rat hippocampal CA1 neurons, forebrain ischemia induces the phosphorylation of the N-methyl-D-aspartate (NMDA) receptor 2A subunit at Ser1232 (phospho-Ser1232). Ser1232 phosphorylation is catalyzed by cyclin-dependent kinase 5 (Cdk5). Inhibiting endogenous Cdk5, or perturbing interactions between Cdk5 and NR2A subunits, abolished NR2A phosphorylation at Ser1232 and protected CA1 pyramidal neurons from ischemic insult. Thus, we conclude that modulation of NMDA receptors by Cdk5 is the primary intracellular event underlying the ischemic injury of CA1 pyramidal neurons.