突触长时程增强形成机制的研究进展

高等动物脑内突触传递的可塑性是近30年来神经科学研究的热点,突触传递长时程增强（long-term potentiation,LTP)是神经元可塑性的反映,其形成主要与突触后机制有关。过去关于LTP机制的研究主要集中于N－甲基－D门冬氨酸（NMDA）受体的特征及该受体被激活后的细胞内级联反应,现认为脑内存在只具有NMDA受体而不具有α－氨基羟甲基恶唑丙酸（AMPA）受体的“静寂突触（silent synapse)”,这一概念的提出,使人们认识到AMPA受体在LTP表达的突触后机制中的重要作用。     

成年小鼠前脑NMDA受体参与神经元的动作电位发放

谷氨酸是中枢神经系统主要的快速兴奋性递质。AMPA受体和海人藻酸受体主要参与突触传递,而NMDA受体主要参与突触可塑性。基因操作的方法增强NMDA受体的功能,可以增强动物在正常生理状态下的学习能力,及在组织损伤情况下的反应敏感性。NMDA受体参与生理功能的主要机制是长时程增强（long—term potentiation,LTP）。我们的研究表明,NMDA受体不仅参与刺激前扣带皮层的第五层细胞或刺激白质诱导的突触反应,而且参与在胞体施加去极化跃阶电流诱导的动作电位的发放。钙一钙调蛋白敏感的腺苷酸环化酶1（adenylyl cyclase 1,AC1）和cAMP信号通路可能介导了这些反应。由于扣带皮层神经元在伤害性刺激和痛中发挥重要作用,我们的结果为前脑NMDA受体参与突触传递和动作电位发放,以及与前脑相关的行为,如感受伤害性刺激和痛,提供了一个新的机制。     

培养大鼠颈上神经节单烟碱受体通道及突触电流的膜片钳研究

在培养１─２周的大鼠颈上神经节交感神经元标本上,用膜片钳技术记录了单烟碱受体通道电流及胆碱能突触电流,并分析了它们之间的关系。单烟碱受体通道至少有三种亚导状态,即１５ｐＳ,２７ｐＳ,３８ｐＳ,其中以２７ｐＳ最常见。通道有两种开放模式,即单个短促开放与长串开放。对应的平均开放时间分别为τ＿１＝１．７１ｍｓ,τ＿２＝１２．２４ｍｓ。对自发突触电流的分析表明,其下降相的衰减时间常数（τ＝１５．７±１ｍｓ）与上述长串开放的持续时间相当,提示在突触传递过程中,突触前末梢释放的ＡＣｈ引起了突触后神经元烟碱受体通道的长串开放。     

谷氨酸性突触在痛觉和记忆中的突触和分子机制

谷氨酸是哺乳动物脑中的兴奋性递质。中枢神经系统的谷氨酸性突触广泛参与痛觉传递,突触可塑性和递质的调节。谷氨酸的NMDA受体参与前脑相关的学习及功能。在这篇综述中,我们提出前脑的NMDA受体通过增强谷氨酸性突触传递导致长期性的炎痛。具有增强NMDA受体功能的小鼠会产生更多的慢性痛。NMDA NR2B受体抑制剂在未来可能被用来控制人类的慢性痛。     

N-甲基-D-天氡氨酸受体的分子结构与生理功能

N-甲基-D-天氡氨酸（NMDA）受体是离子型谷氨酸受体的一种亚型,在中枢神经系统的突触传递和突触可塑性调节中起着重要的作用。延长NMDA受体活动时间将导致兴奋毒性。NMDA受体是一个具有多个结合位点的大分子复合物,其生理特性同异聚体通道的装配密切相关。NMDA受体的异常会导致一些认知功能的缺失,这为治疗性药物开发提供了靶点。     

N-甲基-D-天氡氨酸受体的分子结构与生理功能

NMDA（N-甲基-D-天氡氨酸）受体是离子型谷氨酸受体的一种亚型,在中枢神经系统的突触传递和突触可塑性调节中起着重要的作用。生物体内已经发现了三种NMDA受体亚基,通过基因的选择性剪切可产生多种亚单位。NMDA受体是一个具有多个结合位点的大分子复合物,其生理特性同异聚体通道的装配密切相关。NMDA受体的异常会导致一些认知功能的缺失,这为治疗性药物开发提供了靶点。     

AMPA受体转运及其调控的分子机制

α-氨-3-羟基-5-甲基-4-异恶唑丙酸受体（α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors,AMPA receptors）介导中枢神经系统（CNS）绝大多数快兴奋性突触传递,在学习、记忆和认知等方面具有重要功能. 突触AMPA受体的数量、分布和亚基组成是调节突触传递强度的一个主要机制,与AMPA受体转运密切相关. 最新研究显示,异常的AMPA受体转运与阿尔茨海默病（Alzheimer’s disease,AD）、脆性X综合征(fragile X syndrome, FXS)等神经疾病有关. 本文主要针对AMPA受体转运及其调控的分子机制做一综述,以期为AD、FXS等神经疾病提供新的治疗靶点和途径.     

NMDA受体的结构及其生理作用

N-甲基-D-天冬氨酸（NMDA）受体是离子型兴奋性谷氨酸受体的一种亚型,生物体内已发现了3种NMDA受体亚基,且通过选择性剪接至少存在7种亚型,形成具有功能的多结合位点的大分子复合物。NMDA受体在中枢神经系统的突触传递、突触可塑性、学习记忆等生理过程中发挥着重要作用,且NMDA受体的异常会导致-些精神疾病及认知功能的障碍。     

NMDA受体参与皮层内突触结构和功能的调节

在中枢神经系统内神经细胞的树突棘是突触信息传递的重要部位,树突棘的体积和密度影响神经环路的功能。2007年美国加利福尼亚大学的SilaK．Ultanir等人在皮层NRl亚基（是NMDA受体的必要组分）基因敲除的小鼠上发现NMDA受体对树突棘的发育有重要影响。急性分离出生后三周内小鼠的脑片,用电压钳全细胞记录的方法,发现在皮层2／3层的锥体细胞中,AMPA受体介导的微小兴奋性突触后电流（mEP-SC）的幅度和频率均明显增大。     

突触前代谢型谷氨酸受体调节神经递质的释放

谷氨酸通过激活离子型受体（iGluR)介导快速兴奋性突触传递,参与脑内几乎所有生理过程。谷氨酸过量释放可导致与脑缺血,缺氧及变性疾病有关的兴奋毒作用,最终引起神经元的死亡。代谢型谷氨酸受体（mGluRs)是一个与G－蛋白偶联的受体家族,分三型共八个亚型。其中Ⅱ和Ⅲ型mGluRs主要位于突触前,发挥对谷氨酸释放的负反馈调节。Ⅲ型mGluRs中的mGluR7位于谷氨酸能末梢突触前膜的活性区,发挥自身受体的作用,对正常情况下突触传递过程的谷氨酸释放进行负反馈调节;而属于Ⅱ型的mGluR2及属于Ⅲ型的mGluR4和mGluR8,则位于远离突有膜活性区的外突触区,因而正常突触传递过程中释放的谷氨酸量不能激活它们。只有在突触传递增强的情况下才被激活,抑制递质的释放。国外,mGluRs还分布在GABA能纤维末梢,通过突触前机制抑制GABA的释放。对突触前膜受体尤其是位于外突触区的mGluRs受体的研究,将有可能开发出理想的工具药,从而预防和阻止谷氨酸过量释放引起的神经毒及神经元的死亡。     

Not too much and not too little

We tend to think in black and white terms of good versus bad alleles and their meaning for disease. However, in doing so, we ignore the potential importance of heterozygous alleles.The structure and function of any protein is determined by its amino acid sequence. Thus, the substitution of one amino acid for another can alter the activity of a protein or its function. Mutations—or rather, polymorphism, once they become fixed in the population—can be deleterious, such that the altered protein is no longer able to fulfil its role with potentially devastating effects on the cell. Rarely, they can improve protein function and cell performance. In either case, any changes in the amino acid sequence, whether they affect only one amino acid or larger parts of the protein, are encoded by polymorphisms in the nucleotide sequence of that protein''s gene. For any given polymorphism, diploid organisms with two sets of chromosomes can therefore exist in either a heterozygous state or one of two homozygous states. When the polymorphism is rare, most individuals are homozygous for the ‘wild-type'' state, some individuals are heterozygous and a few are homozygous for the rare polymorphic variant. Conversely, if the polymorphism occurs in 50% of the alleles, the heterozygous state is common.At first glance, the deleterious homozygous state seems to be something that organisms try to avoid: close relatives usually do not breed, probably to prevent the homozygous accumulation of deleterious alleles. Thus, human cultural norms, founded in our biology, actively select for heterozygosity as many civilizations and societies regard incest as a social taboo. The fields of animal husbandry and conservation biology are littered with information about the significant positive correlation between genetic diversity, evolutionary advantage and fitness [1]. In sexually reproducing organisms, heterozygosity is generally regarded as ‘better'' in terms of adaptability and evolutionary advantage.Why then do we seldom, if ever, regard allelic heterozygosity as an advantage when it comes to genes linked with health and disease? Perhaps it is because we tend to distinguish between the ‘good'' allele, the ‘bad'' allele and the ‘ugly'' heterozygote—since it is burdened with one ‘bad'' allele. Maybe this attitude is a remnant of the outdated ‘one gene, one disease'' model, or of the early studies on inheritable diseases that focused on monogenic or autosomal-dominant genetic disorders. Even modern genetics almost always assigns ‘risk'' to an allele that is associated with a health condition or disadvantaged phenotype; clearly, then, the one homozygous state must have an advantage—sometimes referred to as wild-type—but the heterozygote is often ignored altogether.Maybe we also shun heterozygosity because it is hard to prove, beyond a few examples, that it might offer advantage. A 2010 paper published in Cell claimed that heterozygosity of the lth4A locus conveys protection against tuberculosis [2]. There is a mechanistic basis for the claim: lth4A encodes leukotriene A4 hydrolase, which is the final catalyst to synthesize leukotriene B4, an efficient pro-inflammatory eicosanoid. However, an extensive case–control study could not confirm the association between heterozygosity and protection against tuberculosis [3]. Therefore, many in the field dismiss the prior claim to protection conferred by the heterozygous state.Yet, we know that most biochemical and physiological processes are highly complex systems that involve multiple, interlinked steps with extensive control and feedback mechanisms. Heterozygosity might be one strategy by which an organism maintains flexibility, as it provides more than one allele to fall back on, should conditions change. We may therefore hypothesize that heterozygosity can be either a risk or an advantage, depending on the penetrance or dominance of the alleles. Indeed, there are a few cases in which heterozygosity confers some advantage. For example, individuals who are homozygous for the CCR5 deletion polymorphism (D32/D32) are protected against HIV1 infection, whereas CCR5/D32 heterozygotes have a slower progression to acquired immunodeficiency syndrome (AIDS). In sickle-cell anaemia, heterozygotes have a protective advantage against malaria, whereas the homozygotes either lack protection or suffer health consequences. Thus, although heterozygosity might not create a general fitness advantage, it is advantageous under certain specific conditions, namely the presence of the malaria parasite.In most aspects of life, there are few absolutes and many shades of grey. The ‘normal'' range of parameters in medicine is a clear example of this: optimal functioning of the relevant physiological processes depends on levels that are ‘just right''. As molecular and genetic research tackles the causes and risk factors of complex diseases, we may perhaps find more examples of how heterozygosity at the genetic level conveys health advantages in humans. As the above example regarding tuberculosis indicates, it is difficult to demonstrate any advantage of the heterozygous state. We simply need to be receptive to such possibilities, and improve and reconcile our understanding of allelic diversity and heterozygosity. Researchers working on human disease could benefit from the insights of evolutionary biologists and breeders, who are more appreciative of the heterozygous state.     

Born too soon

In this Letter, the author walks through 'Memory Lane'. She reflects upon the birth, growth and developmental trajectory of her third child who was born too soon, in a major Hospital in London. Her aim is to share her knowledge and experiences with other parents and professionals. The author acknowledges the feelings which is so common amongst mothers of preterm babies i.e. that the baby does not belong to them. Moreover, she reflects upon her participation in caring for her daughter, how overwhelming it all was and her joy when her child left hospital and is a healthy teenager.