二甲双胍调节初级视觉皮层兴奋性和抑制性平衡及改善视觉功能的研究（英文）

大脑皮层中兴奋和抑制系统之间的动态平衡决定了皮层神经元对刺激的反应特性.已有研究表明,二甲双胍能够诱导γ-氨基丁酸受体向突触后膜聚集,增强神经系统的抑制效果.本课题进一步探讨了二甲双胍对初级视觉皮层兴奋和抑制系统平衡的调节作用,以及其改善小鼠视觉功能的潜力.实验使用成年雄性小鼠,实验组(metformin) 10只每天给予二甲双胍250 mg/kg,对照组(control) 6只每天给予0.3 ml生理盐水,灌胃处理3周.结果发现二甲双胍可以显著升高囊泡GABA转运蛋白VGAT和突触后抑制性递质受体相关蛋白Gephyrin的合成.此外,它显著降低突触后兴奋性受体Glu A1和Glu N1的表达.多通道电极电生理记录结果显示,二甲双胍作用下小鼠初级视觉皮层的自发放和诱发放显著降低,而信噪比、方向和方位选择性显著增加.实验结果表明,二甲双胍可以通过降低兴奋突触、增强抑制突触,调节初级视皮层的兴奋——抑制平衡,提高信息处理能力,增强视觉功能.     

TrkB受体依赖的PV神经元调控小鼠视觉方位辨别能力的机制

神经营养因子-酪氨酸受体激酶B （tyrosine receptor kinase B,TrkB）信号通路在调控初级视皮层（primary visual cortex,V1）兴奋与抑制平衡上发挥着重要的作用,以往的研究揭示了其通过增加兴奋性传递效率来调控皮层兴奋性水平的机制,却并未阐明TrkB受体如何通过抑制系统来调控兴奋与抑制平衡,进而影响视觉皮层功能。为了探讨TrkB信号通路如何特异性地调控最主要的抑制性神经元——PV神经元进而对小鼠视觉皮层功能产生影响,本研究通过病毒特异性地降低V1区的PV神经元上TrkB受体的表达水平,并通过在体多通道电生理手段记录初级视皮层抑制性与兴奋性神经元功能变化,通过行为学实验测试小鼠的方位辨别能力改变。结果表明,初级视觉皮层中的PV抑制性神经元上的TrkB受体表达减少会显著增加兴奋性神经元的反应强度,减弱抑制性神经元与兴奋性神经元的方位辨别能力,增加二者的信噪比,但是小鼠个体水平的方位辨别能力出现下降。这些结果说明,TrkB信号通路并非单纯通过增加靶向PV神经元的兴奋性传递来调控PV神经元的功能,其对神经元信噪比的影响也并非由于抑制系统的增强所致。     

二甲双胍激活AMPK对高糖诱发内皮细胞氧化应激的影响

目的探讨二甲双胍激活AMPK对高糖诱发的血管内皮细胞氧化应激过程的影响。方法高糖培养诱导人主动脉内皮细胞HAEC氧化应激,用AMPK激动剂5-氨基咪唑-4-甲酰胺-1-B-呋喃核糖苷(AICAR,2 mmol/L)和二甲双胍(metformin,2mmol/L)进行干预,分别用Western blot和免疫荧光检测内皮细胞AMPK/T-172磷酸化蛋白表达水平及细胞内氧化应激相关蛋白p47phox和p67phox的表达。雄性C57BL/6小鼠随机分为正常对照组(NC,n=10)、链脲菌素诱导糖尿病模型组(DM,n=10)和二甲双胍干预糖尿病模型组(MT,n=10),造模成功后MT组经饮水给予二甲双胍50mg/(kg/d),NC组、DM组给予正常饮水。期间定期测定小鼠体重,并检测各阶段血糖。二甲双胍干预一周后处死小鼠,取主动脉做免疫组化观察血管内皮细胞的氧化应激状态。结果在内皮细胞中二甲双胍可通过激活AMPK来抑制NADPH氧化酶胞质内亚基p47phox和p67phox的表达。动物实验显示,与糖尿病模型组小鼠相比,二甲双胍干预组小鼠血糖降低,体重增加,差异均有统计学意义(P0.05)。免疫组化分析显示,小鼠主动脉血管内皮细胞的氧化应激标志性产物3-NT(3-nitrotyrosine),MDA(malondialdehyde)和HNE(4-hydroxy-2-nonenal)的水平均明显降低。结论二甲双胍可通过激活AMPK来缓解内皮细胞中出现的氧化应激,可能对糖尿病血管并发症具有预防和治疗作用。     

二甲双胍抑制H1299细胞迁移及其机制研究

该文主要研究二甲双胍(metformin, Met)对肺腺癌H1299细胞增殖、迁移和凋亡的影响,并探讨其可能作用机制。利用显微镜观察二甲双胍处理后细胞形态,划痕实验检测二甲双胍对细胞迁移的影响; Annexin V/PI标记,流式检测二甲双胍对细胞凋亡的影响; 5-乙炔基-2’脱氧尿嘧啶(Edu)法检测二甲双胍对细胞增殖的影响。结果表明,二甲双胍能改变H1299细胞形态且能显著抑制细胞迁移;二甲双胍不能诱导H1299细胞凋亡;二甲双胍能抑制H1299细胞增殖。进一步研究发现,二甲双胍能下调p-ERK和p-MEK蛋白水平,同时增加E-Cadherin和减少FAK、vimentin蛋白表达,说明二甲双胍主要通过抑制ERK信号通路抑制H1299细胞增殖和迁移,并通过上调E-Cadherin、下调FAK、vimentin使H1299细胞迁移受到明显抑制,为二甲双胍应用于肺腺癌的预防及治疗提供了指导依据。     

大鼠丘脑侧后核到初级视皮层突触传递的短时程可塑性

大鼠丘脑侧后核(lateral posterior thalamic nucleus,LP nucleus)到初级视皮层的突触连接是膝体外视觉通路的重要组成部分.运用场电位记录和电泳的方法在位研究了该视觉回路突触传递的短时程可塑性.结果表明,无论是运用双脉冲刺激还是串刺激都能观察到明显的短时程抑制特性.电泳荷包牡丹碱(bicuculline)和2-hydroxy-saclofen使该抑制作用减弱,电泳钙离子使抑制加强,电泳APV对抑制作用没有明显影响.所以突触前递质释放水平的改变,和γ-氨基丁酸(GABA)能受体（尤其是GABA_B受体）的活动都会影响该回路突触传递的短时程可塑性,而N-甲基-D-天冬氨酸(NMDA)受体则几乎没有作用.该回路很强的短时程抑制特性可能与LP核在视觉注意中的作用有关.     

猫初级视皮层内GIu/GABA表达比率的衰老性变化

最近的一些研究结果显示,视皮层内抑制性递质系统作用减弱可能是导致老年性视觉功能衰退的重要因素.是否皮层内兴奋性递质系统亦伴随衰老而发牛改变并影响皮层内神经兴奋与抑制的平衡尚不清楚.为此,利用Nissl染色和免疫组织化学染色方法以及Image-Pro Express图像分析软件对青、老年猫初级视皮层(17区)内各层神经元密度、兴奋性递质谷氨酸免疫反应阳性(Glu-immunoreactive,Glu-IR)神经元密度以及抑制性递质γ-氨基丁酸免疫反应阳性(γ-aminobutyric acid.immunoreactive,GABA-IR)神经元密度进行了统汁分析.结果显示,青、老年猫初级视皮层各层神经元密度均没有明显的年龄性差异(P>0.05);与青年猫相比,老年猫初级视皮层Glu-IR、GABA-IR神经元密度均显著减少(P<0.01),而Glu.IR/GABA.IR神经元密度比率去却显著增大(P<0.01).结果提示,老年猫初级视皮层内兴奋性递质系统作用相对增强,而抑制性递质系统的作用相对减弱,导致皮层内兴奋-抑制平衡关系失调,这可能是引起老年个体视觉功能衰退的重要原因之一.     

二甲双胍对胶质母细胞瘤细胞的抑制作用研究

为了探究二甲双胍对不同胶质母细胞瘤U87细胞、GL261细胞及C6细胞增殖的影响,选取小鼠GBM细胞GL261细胞系、大鼠GBM细胞C6细胞系及人源GBM细胞U87MG细胞系,使用二甲双胍处理,通过CCK-8法检测细胞增殖活性;细胞实时荧光检测细胞凋亡水平;平板克隆实验检测GBM细胞克隆形成能力;CCK-L法检测胞内ATP水平;Western blot检测Akt及其磷酸化水平。结果显示,与对照组相比,随着作用浓度增加,二甲双胍显著抑制GBM细胞增殖活性,影响细胞形态;与对照组相比,同一作用浓度下,二甲双胍提高了GBM细胞凋亡水平,抑制了GBM细胞克隆形成能力,降低了GBM胞内ATP的产生;二甲双胍处理24 h后,GBM细胞内p-Akt表达显著下调,Akt无明显变化。结果表明,二甲双胍在体外可抑制多种GBM细胞的增殖、克隆,降低胞内ATP水平,其机制可能与Akt磷酸化水平相关,研究结果为进一步探索二甲双胍对胶质母细胞瘤的作用机制提供了体外研究理论基础。     

二甲双胍增强胰腺癌放疗敏感性的体外及体内实验研究

目的:探讨二甲双胍对胰腺癌细胞和胰腺癌裸鼠移植瘤放疗敏感性的影响。方法:体外培养人胰腺癌Bx PC-3和As PC-1细胞,分为二甲双胍处理组和未处理组,处理组给予10 mmol/L二甲双胍作用48小时后分别给予0、1、2、4、6、8Gy射线对两种细胞进行照射,运用克隆形成实验,Giemsa染色后计算克隆形成率及SF2,并拟合细胞存活曲线。应用裸鼠皮下注射胰腺癌细胞,建立两种细胞的裸鼠移植瘤模型,裸鼠肿瘤体积达到100 mm~3时,作为0天,并开始分组,每种移植瘤使用24只裸鼠随机分为4组:生理盐水对照组、单纯二甲双胍治疗组、单纯照射组、二甲双胍+照射组,二甲双胍处理组每天给予250 mg/kg(50μL/每只)腹腔注射,对照组仅给予等量生理盐水注射(50μL/每只)。每4天用游标卡尺测量移植瘤的长径和宽径,并绘制生长曲线。当对照组体积达到200 mm~3时,照射组和联合组,给予一次性照射6Gy射线,当对照组体积达到1000 mm~3时,将裸鼠进行麻醉,剥出皮下移植瘤,进行称量和保存,并计算抑瘤率。结果:两细胞系经过二甲双胍处理后,经2、4、6、8Gy照射后存活分数明显低于未处理组(P0.01),随着照射剂量的增大,克隆形成数量明显减少,两个细胞系经二甲双胍处理后进行照射,其SF2、D0,N值均较未处理组明显减少(P0.01),表明经二甲双胍处理后,Bx PC-3细胞和As PC-1细胞的放射敏感性增强,增敏比分别为1.2368和1.1179。二甲双胍和放射联合处理组的体积、瘤重均明显小于对照组和单独处理组,Bx PC-3和As PC-1移植瘤的抑瘤率分别为62.14%、61.53%,均明显高于各自单独处理组(P0.01或P0.05)。结论:二甲双胍能够增强胰腺癌的放疗敏感性,在临床上具有潜在的应用价值。     

二甲双胍联合放射线照射对鼻咽癌细胞CNE-1增殖的影响

目的:探讨二甲双胍联合放射线照射对鼻咽癌细胞CNE-1增殖的影响。方法:分别给予鼻咽癌细胞CNE-1二甲双胍(5m M)、2Gy放射线照射、二甲双胍(5 m M)联合2Gy放射线照射处理后,采用MTT实验、克隆形成实验检测和比较其细胞增殖抑制率和克隆形成抑制率。结果:MTT实验结果显示:与二甲双胍组或2Gy放射线照射组相比,二甲双胍联合放射线照射组细胞增殖抑制率显著升高,差异具有统计学意义(P0.05);克隆形成实验结果显示,与二甲双胍组或2Gy放射线照射组相比,二甲双胍联合放射线照射组细胞克隆形成抑制率显著升高,差异具有统计学意义(P0.05)。结论:二甲双胍联合放射线照射能够有效的抑制鼻咽癌细胞CNE-1的增殖。     

二甲双胍和西格列汀对胰岛素抵抗糖尿病前期KKAy小鼠胰岛β细胞功能的影响*

目的:探讨二甲双胍和西格列汀对胰岛素抵抗糖尿病前期KKAy小鼠胰岛β细胞功能的影响及其机制。方法:将30只6周龄KKAy小鼠随机分为普通饲料喂养组(C组,n=10)及高脂饲料喂养组(n=20),8周龄时将高脂饮食喂养的KKAy小鼠随机分为两组:二甲双胍干预组(Met组,n=10)和西格列汀干预组(SP组,n=10),持续灌胃8周。用口服糖耐量实验(OGTT)检测葡萄糖水平。检测空腹血清胰岛素及血浆脂质水平,计算胰岛素释放指数(HOMA-β)及胰岛素抵抗指数(HOMA-IR)。留取KKAy小鼠胰腺,连续切片分别胰岛素、胰高血糖素免疫荧光染色,ki67/INS双标记分析β细胞增殖情况、凋亡情况。Western blot方法测定胰腺转录因子PDX-1和MafA蛋白表达情况。结果:① OGTT结果提示,与C组比较,Met和SP组KKAy小鼠的空腹血糖、口服葡萄糖后30、60及120 min的血糖均显著降低(P均＜0.01),血糖时间曲线下面积(AUC)显著降低(P＜0.01,P＜0.01)。与Met组比较,SP组口服葡萄糖后30及60 min的血糖无明显统计学差异,120 min的血糖显著降低(P＜0.05),两组AUC无统计学差异。② 胰岛素耐量试验(ITT)结果提示,与C比较,Met和SP组KKAy小鼠的空腹血糖、注射胰岛素后30、60及90 min的血糖显著减低,ITT血糖曲线下面积(AUC)显著升高(P＜0.01),而Met和SP组之间比较无明显统计学差异。③ C组胰岛中β细胞区域亮度较低,边缘散乱,给予二甲双胍后,β细胞区域及亮度有所增加;给予西格列汀治疗后,β细胞区域及亮度显著增加。C组胰岛中,α细胞在胰岛中分布无序,亮度较大。给予二甲双胍后,α细胞区域有所减少,亮度有所降低,一定程度向胰岛边缘的分布;给予西格列汀后,α细胞区域明显减少,亮度显著降低,在胰岛边缘分布。④ 与C组比较,Met组和SP组胰腺MafA表达水平明显升高,分别为1.63倍,1.58倍(P＜0.01,P＜0.01)。各组间胰腺PDX-1表达情况无显著差异。结论:对胰岛素抵抗糖尿病前期KKAy小鼠,给予二甲双胍可以维持胰岛的功能和形态,给与西格列汀可能促进β细胞增殖,提高胰岛素转录因子MafA的表达水平,防止糖尿病的发生发展。     

GABA and neuroligin signaling: linking synaptic activity and adhesion in inhibitory synapse development

GABA-mediated synaptic inhibition is crucial in neural circuit operations. In mammalian brains, the development of inhibitory synapses and innervation patterns is often a prolonged postnatal process, regulated by neural activity. Emerging evidence indicates that gamma-aminobutyric acid (GABA) acts beyond inhibitory transmission and regulates inhibitory synapse development. Indeed, GABA(A) receptors not only function as chloride channels that regulate membrane voltage and conductance but also play structural roles in synapse maturation and stabilization. The link from GABA(A) receptors to postsynaptic and presynaptic adhesion is probably mediated, partly by neuroligin-reurexin interactions, which are potent in promoting GABAergic synapse formation. Therefore, similar to glutamate signaling at excitatory synapse, GABA signaling may coordinate maturation of presynaptic and postsynaptic sites at inhibitory synapses. Defining the many steps from GABA signaling to receptor trafficking/stability and neuroligin function will provide further mechanistic insights into activity-dependent development and possibly plasticity of inhibitory synapses.     

Processing in layer 4 of the neocortical circuit: new insights from visual and somatosensory cortex

Recent experimental and theoretical results in cat primary visual cortex and in the whisker-barrel fields of rodent primary somatosensory cortex suggest common organizing principles for layer 4, the primary recipient of sensory input from the thalamus. Response tuning of layer 4 cells is largely determined by a local interplay of feed-forward excitation (directly from the thalamus) and inhibition (from layer 4 inhibitory interneurons driven by the thalamus). Feed-forward inhibition dominates excitation, inherits its tuning from the thalamic input, and sharpens the tuning of excitatory cells. Recurrent excitation enhances responses to effective stimuli.     

Retrograde GABA signaling adjusts sound localization by balancing excitation and inhibition in the brainstem

Central processing of acoustic cues is critically dependent on the balance between excitation and inhibition. This balance is particularly important for auditory neurons in the lateral superior olive, because these compare excitatory inputs from one ear and inhibitory inputs from the other ear to compute sound source location. By applying GABA(B) receptor antagonists during sound stimulation in vivo, it was revealed that these neurons adjust their binaural sensitivity through GABA(B) receptors. Using an in vitro approach, we then demonstrate that these neurons release GABA during spiking activity. Consequently, GABA differentially regulates transmitter release from the excitatory and inhibitory terminals via feedback to presynaptic GABA(B) receptors. Modulation of the synaptic input strength, by putative retrograde release of neurotransmitter, may enable these auditory neurons to rapidly adjust the balance between excitation and inhibition, and thus their binaural sensitivity, which could play an important role as an adaptation to various listening situations.     

Golgi Cell-Mediated Activation of Postsynaptic GABA(B) Receptors Induces Disinhibition of the Golgi Cell-Granule Cell Synapse in Rat Cerebellum

In the cerebellar glomerulus, GABAergic synapses formed by Golgi cells regulate excitatory transmission from mossy fibers to granule cells through feed-forward and feedback mechanisms. In acute cerebellar slices, we found that stimulating Golgi cell axons with a train of 10 impulses at 100 Hz transiently inhibited both the phasic and the tonic components of inhibitory responses recorded in granule cells. This effect was blocked by the GABA(B) receptor blocker CGP35348, and could be mimicked by bath-application of baclofen (30 μM). This depression of IPSCs was prevented when granule cells were dialyzed with GDPβS. Furthermore, when synaptic transmission was blocked, GABA(A) currents induced in granule cells by localized muscimol application were inhibited by the GABA(B) receptor agonist baclofen. These findings indicate that postsynaptic GABA(B) receptors are primarily responsible for the depression of IPSCs. This inhibition of inhibitory events results in an unexpected excitatory action by Golgi cells on granule cell targets. The reduction of Golgi cell-mediated inhibition in the cerebellar glomerulus may represent a regulatory mechanism to shift the balance between excitation and inhibition in the glomerulus during cerebellar information processing.     

The enigma of transmitter-selective receptor accumulation at developing inhibitory synapses

The control of synaptic inhibition is crucial for normal brain function. More than 20 years ago, glycine and gamma-aminobutyric acid (GABA) were shown to be the two major inhibitory neurotransmitters. They can be released independently from different terminals or co-released from the same terminal to activate postsynaptic glycine and GABA(A) receptors. The anchoring protein gephyrin is involved in the postsynaptic accumulation of both glycine and GABA(A) receptors. In lower brain regions, both receptors can be concentrated in synapses, whereas in higher brain regions, glycine receptors are mostly excluded from postsynaptic sites. The activation of glycine and/or GABA(A) receptors determines the strength and precise timing of inhibition. Therefore, tight regulation of postsynaptic glycine versus GABA(A) receptor localization is crucial for optimizing synaptic inhibition in neurons. This review focuses on recent findings and discusses questions concerning the specificity of postsynaptic inhibitory neurotransmitter receptor accumulation during inhibitory synapse formation and development.     

Fast and slow excitation of inhibitory cells in the CA3 region of the hippocampus

Pyramidal cells form excitatory synaptic connections with local inhibitory neurons in the hippocampus. This recurrent synapse plays a crucial stabilizing role in the control of hippocampal activity, since it transforms pyramidal cell population. Using a combination of dual recording from presynaptic and postsynaptic cells and anatomical techniques, we show that these synaptic connections often comprise a single site for liberation of excitatory transmitter. The resulting excitatory postsynaptic potentials (EPSCs) have a fast time course and a similar amplitude to miniature EPSCs recorded in tetrodotoxin and cobalt. In contrast, activation of metabotropic glutamate receptors (mGluRs) by transmitter liberated during repetitive activation of these synapses produces an excitation with a much slower time course. In addition to somatodendritic mGluRs, which excite inhibitory cells, a different species of mGluR is present on inhibitory cell terminals. This mGluR is activated by higher concentrations of the agonist t-1-amino-cyclopentyl–1,3-decarboxylate and acts to reduce γ-aminobutyric acid release. mGluRs, thus, have a dual action to enhance and to depress synaptic inhibition in the hippocampus. © 1995 John Wiley & Sons, Inc.     

Balancing feed-forward excitation and inhibition via Hebbian inhibitory synaptic plasticity

It has been suggested that excitatory and inhibitory inputs to cortical cells are balanced, and that this balance is important for the highly irregular firing observed in the cortex. There are two hypotheses as to the origin of this balance. One assumes that it results from a stable solution of the recurrent neuronal dynamics. This model can account for a balance of steady state excitation and inhibition without fine tuning of parameters, but not for transient inputs. The second hypothesis suggests that the feed forward excitatory and inhibitory inputs to a postsynaptic cell are already balanced. This latter hypothesis thus does account for the balance of transient inputs. However, it remains unclear what mechanism underlies the fine tuning required for balancing feed forward excitatory and inhibitory inputs. Here we investigated whether inhibitory synaptic plasticity is responsible for the balance of transient feed forward excitation and inhibition. We address this issue in the framework of a model characterizing the stochastic dynamics of temporally anti-symmetric Hebbian spike timing dependent plasticity of feed forward excitatory and inhibitory synaptic inputs to a single post-synaptic cell. Our analysis shows that inhibitory Hebbian plasticity generates 'negative feedback' that balances excitation and inhibition, which contrasts with the 'positive feedback' of excitatory Hebbian synaptic plasticity. As a result, this balance may increase the sensitivity of the learning dynamics to the correlation structure of the excitatory inputs.     

Role of GABAA-Mediated Inhibition and Functional Assortment of Synapses onto Individual Layer 4 Neurons in Regulating Plasticity Expression in Visual Cortex

Layer 4 (L4) of primary visual cortex (V1) is the main recipient of thalamocortical fibers from the dorsal lateral geniculate nucleus (LGN_d). Thus, it is considered the main entry point of visual information into the neocortex and the first anatomical opportunity for intracortical visual processing before information leaves L4 and reaches supra- and infragranular cortical layers. The strength of monosynaptic connections from individual L4 excitatory cells onto adjacent L4 cells (unitary connections) is highly malleable, demonstrating that the initial stage of intracortical synaptic transmission of thalamocortical information can be altered by previous activity. However, the inhibitory network within L4 of V1 may act as an internal gate for induction of excitatory synaptic plasticity, thus providing either high fidelity throughput to supragranular layers or transmittal of a modified signal subject to recent activity-dependent plasticity. To evaluate this possibility, we compared the induction of synaptic plasticity using classical extracellular stimulation protocols that recruit a combination of excitatory and inhibitory synapses with stimulation of a single excitatory neuron onto a L4 cell. In order to induce plasticity, we paired pre- and postsynaptic activity (with the onset of postsynaptic spiking leading the presynaptic activation by 10ms) using extracellular stimulation (ECS) in acute slices of primary visual cortex and comparing the outcomes with our previously published results in which an identical protocol was used to induce synaptic plasticity between individual pre- and postsynaptic L4 excitatory neurons. Our results indicate that pairing of ECS with spiking in a L4 neuron fails to induce plasticity in L4-L4 connections if synaptic inhibition is intact. However, application of a similar pairing protocol under GABA_ARs inhibition by bath application of 2μM bicuculline does induce robust synaptic plasticity, long term potentiation (LTP) or long term depression (LTD), similar to our results with pairing of pre- and postsynaptic activation between individual excitatory L4 neurons in which inhibitory connections are not activated. These results are consistent with the well-established observation that inhibition limits the capacity for induction of plasticity at excitatory synapses and that pre- and postsynaptic activation at a fixed time interval can result in a variable range of plasticity outcomes. However, in the current study by virtue of having two sets of experimental data, we have provided a new insight into these processes. By randomly mixing the assorting of individual L4 neurons according to the frequency distribution of the experimentally determined plasticity outcome distribution based on the calculated convergence of multiple individual L4 neurons onto a single postsynaptic L4 neuron, we were able to compare then actual ECS plasticity outcomes to those predicted by randomly mixing individual pairs of neurons. Interestingly, the observed plasticity profiles with ECS cannot account for the random assortment of plasticity behaviors of synaptic connections between individual cell pairs. These results suggest that connections impinging onto a single postsynaptic cell may be grouped according to plasticity states.