Coupling between NMDA receptor and acid-sensing ion channel contributes to ischemic neuronal death

Acid-sensing ion channels (ASICs) composed of ASIC1a subunit exhibit a high Ca2+ permeability and play important roles in synaptic plasticity and acid-induced cell death. Here, we show that ischemia enhances ASIC currents through the phosphorylation at Ser478 and Ser479 of ASIC1a, leading to exacerbated ischemic cell death. The phosphorylation is catalyzed by Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, as a result of activation of NR2B-containing N-methyl-D-aspartate subtype of glutamate receptors (NMDARs) during ischemia. Furthermore, NR2B-specific antagonist, CaMKII inhibitor, or overexpression of mutated form of ASIC1a with Ser478 or Ser479 replaced by alanine (ASICla-S478A, ASIC1a-S479A) in cultured hippocampal neurons prevented ischemia-induced enhancement of ASIC currents, cytoplasmic Ca2+ elevation, as well as neuronal death. Thus, NMDAR-CaMKII cascade is functionally coupled to ASICs and contributes to acidotoxicity during ischemia. Specific blockade of NMDAR/CaMKII-ASIC coupling may reduce neuronal death after ischemia and other pathological conditions involving excessive glutamate release and acidosis.

Propofol effects on excitatory synaptic efficacy in the CA1 region of the developing hippocarnpus

The anesthetic, propofol, effectively suppresses excitatory synaptic transmission and facilitates long-term depression (LTD) in the CA1 region of the hippocampus. Here, we have examined whether these effects are different in the developing hippocampus. We found that propofol in suppressing whole-cell excitatory postsynaptic currents (EPSC) was more effective in 21 day old rats than either in 7 day old rats or under the condition of high intracellular chloride concentration in 21 day old rats. Furthermore, the propofol concentration to facilitate the NMDA receptor-dependent LTD was lower at postnatal day 21 than at postnatal day 7. Interestingly, the decay time of EPSC was decreased during the development from postnatal day 7 to 21, but it was increased by the recording condition of high intracellular chloride concentration or by propofol administration. All these effects of propofol were dependent on the chloride channel opening. These observations suggest that propofol may induce differential anesthetic effects in the developing hippocampus, at least partially, depending on the intracellular chloride concentration. (c) 2005 Elsevier B.V. All rights reserved.

Stress enables synaptic depression in CA1 synapses by acute and chronic morphine: Possible mechanisms for corticosterone on opiate addiction

The hippocampus, being sensitive to stress and glucocorticoids, plays significant roles in certain types of learning and memory. Therefore, the hippocampus is probably involved in the increasing drug use, drug seeking, and relapse caused by stress. We have studied the effect of stress with morphine on synaptic plasticity in the CA1 region of the hippocampus in vivo and on a delayed-escape paradigm of the Morris water maze. Our results reveal that acute stress enables long-term depression (LTD) induction by low-frequency stimulation (LFS) but acute morphine causes synaptic potentiation. Remarkably, exposure to an acute stressor reverses the effect of morphine from synaptic potentiation ( similar to 20%) to synaptic depression ( similar to 40%), precluding further LTD induction by LFS. The synaptic depression caused by stress with morphine is blocked either by the glucocorticoid receptor antagonist RU38486 or by the NMDA-receptor antagonist D-APV. Chronic morphine attenuates the ability of acute morphine to cause synaptic potentiation, and stress to enable LTD induction, but not the ability of stress in tandem with morphine to cause synaptic depression. Furthermore, corticosterone with morphine during the initial phase of drug use promotes later delayed-escape behavior, as indicated by the morphine-reinforced longer latencies to escape, leading to persistent morphine-seeking after withdrawal. These results suggest that hippocampal synaptic plasticity may play a significant role in the effects of stress or glucocorticoids on opiate addiction.

Morphine withdrawal affects both delayed-escape behaviour in Morris water maze and hippocampal NR2A/2B expression ratio

Repeated low-dose morphine treatment facilitates delayed-escape behaviour of hippocampus-dependent Morris water maze and morphine withdrawal influences hippocampal NMDA receptor-dependent synaptic plasticity. Here, we examined whether and how morphine wit

DE-71-induced apoptosis involving intracellular calcium and the Bax-mitochondria-caspase protease pathway in human neuroblastoma cells In vitro

Polybrominated diphenyl ethers (PBDEs) are used extensively as flame-retardants and are ubiquitous in the environment and in wildlife and human tissue. Recent studies have shown that PBDEs induce neurotoxic effects in vivo and apoptosis in vitro. However, the signaling mechanisms responsible for these events are still unclear. In this study, we investigated the action of a commercial mixture of PBDEs (pentabrominated diphenyl ether, DE-71) on a human neuroblastoma cell line, SK-N-SH. A cell viability test showed a dose-dependent increase in lactate dehydrogenase leakage and 3-(4,5-dimethylthia-zol-2-yl)-2,5-diphenyl-tetrazolium bromide reduction. Cell apoptosis was observed through morphological examination, and DNA degradation in the cell cycle and cell apoptosis were demonstrated using flow cytometry and DNA laddering. The formation of reactive oxygen species was not observed, but DE-71 was found to significantly induce caspase-3, -8, and -9 activity, which suggests that apoptosis is not induced by oxidative stress but via a caspase-dependent pathway. We further investigated the intracellular calcium ([Ca2+](i)) levels using flow cytometry and observed an increase in the intracellular Ca2+ concentration with a time-dependent trend. We also found that the N-methyl d-aspartate (NMDA) receptor antagonist MK801 (3 mu M) significantly reduced DE-71-induced cell apoptosis. The results of a Western blotting test demonstrated that DE-71 treatment increases the level of Bax translocation to the mitochondria in a dose-dependent fashion and stimulates the release of cytochrome c (Cyt c) from the mitochondria into the cytoplasm. Overall, our results indicate that DE-71 induces the apoptosis of ([Ca2+](i)) in SK-N-SH cells via Bax insertion, Cyt c release in the mitochondria, and the caspase activation pathway.

NMDA受体NR1亚单位基因与精神分裂症的连锁分析

目的 了解N-甲基-D-天冬氨酸(NMDA)受体NR1亚单位基因与精神分裂症的连锁关系.方法 选取NR1亚单位基因所在区域的2个微卫星标记D9s1838和D9s1826,对94个符合美国精神障碍诊断与统计手册第4版精神分裂症诊断标准(DSM-Ⅳ)的中国汉族精神分裂症受累同胞对及家系成员共376个个体作基因分型,其中男性194名,女性182名.采用美国国立精神卫生研究所(NIMH)制订的《遗传研究诊断问卷》(DIGS),对家系成员躯体和精神状况进行评定;采用NIMH制订的《遗传研究家族问卷》(FIGS)了解家系结构.选用GENEHUNTER 2.1软件对分型资料进行非参数连锁分析.结果 两点、多点非参数分析最大LOD值均位于D9s1826,分别为1.70(P=0.050),2.08(P=0.015),两者均大于验证性连锁阈值1.2.结论 NR1基因区域微卫星标记与精神分裂症存在验证性连锁关系,提示NR1基因可能为精神分裂症的易感基因之一.