1、突触传递l 概论l 突触类型（电突触、化学突触）(Electrical synapses/Chemical synapses)l 化学突触传递的原理 -神经递质Neurotransmitters(NT)-合成与储存Synthesis and storage -释放 Release -受体与效应器 Receptors and effectors -复原与降解 Recovery and degradation -神经药理学 Neuropharmacologyl 突触整合的原理 兴奋性突触后电位(EPSPs)的整合 树突特征的贡献 抑制(Inhibition)调制(Modulation)Introd
2、uction十九世纪末，人们已认识到信息从一个神经元到另一个神经元的传递发生在神经元间特殊的位点（例：疼痛的反应）突触 Synapse (1897 Charles Sherrington)突触传递 two hypothesis Argued for a century on its physical nature.电突触-Electrical synapse (Proven in 1959 by E.Furshpan and D.Potter in crayfish)化学突触-Chemical synapse 1.1921年Otto Loewi获得可靠证据;2.B.Katz等证明神经肌接头的快
3、速传递是化学介导的 3.1951年John Eccles用玻璃电极研究了哺乳动物中枢神经系统（CNS）的突触传递 4.过去十年,研究分子的新技术显示突触是很复杂的装置 是一项重要的研究主题IntroductionIntroductionOtto Loewi(1873-1961),德国出生的药理学家,乙酰胆碱（acetylcholine）发现者，1936年医学生理学诺贝尔奖获得者 来自1921年复活节周日的梦中灵感的著名实验：发现“迷走物质”“vagusstoff”,后来被证明是乙酰胆碱（acetylcholine）,显示突触传递采用化学信号物质。Types of synapses 突触是神经元
4、特化的连接，是一个神经元与另一个神经元或其他细胞（如肌肉或腺体细胞）接触和交换信息的部位。神经元间信息单向流动，或从神经元流向其靶细胞。前者为突触前（presynaptic）后者接受信息的靶细胞称之为突触后（postsynaptic）。电突触（Electrical synapses）六个connexins形成一个通道，称之为connexon,两个connexon(各来自一个细胞)形成一个gap junction 通道。通道的孔相对较大，直径12 nm,足以允许细胞内离子及许多小分子有机分子透过其直接从一个细胞到另一个细胞。Types of synapses 一个gap junction将两个细
5、胞的神经突起连接在一起。六个connexin亚基构成一个 connexon，两个connexon形成gap junction通道，许多这样的通道构成了一个gap junction。Types of synapses电突触的功能特征：双向等效通过 电耦合 快速,如是大的电突触则从不出错(fail-safe)，因此，一个突触前神经元的动作电位几乎同时会产生一个突触后神经元的动作电位。在无脊椎动物，如小龙虾，在介导逃跑反应的神经通路中的感觉和运动神经元之间常常会看到有电突触。Types of synapses电突触也存在于脊椎动物的神经系统 中枢神经系统各部分均有 在电耦合的神经元间，突触前的动作电
6、位可以引起一个小的离子流，跨过gap junction channels流入另一个神经元，产生突出后电位（postsynaptic potential,PSP)哺乳动物脑由单个电突触产生的PSP通常很小其峰值约1 mV或更小这样，仅凭该电位是不足以触发突触后细胞的动作电位的。哺乳动物电突触具体的作用因脑区不同而不同(如：同步化synchronize;发育协调 developmental coordination;).见教科书，Box 5-2 by Michael V.L.BennettTypes of synapses 电突触：(a)缝隙连接（gap junction）偶联了二个神经元构成一个
7、电突触；(b)一个神经产生一个动作电位导致一个小的离子流通过缝隙连接通道进入另一个神经元，诱导一个突触后电位（PSP）Types of synapses化学突触（化学突触（Chemical synapses）一般概念:突触间隙（synaptic cleft）(2050 nm),充满纤维状细胞外蛋白质混合物，这种细胞间基质的功能之一就是使突触前后细胞膜相互粘附在一起。突触前组分（presynaptic element）,通常是轴突末梢 突触囊泡（synaptic vesicles）(直径50 nm),储存神经递质（neurotransmitter）用于与突触后神经元通讯 分泌颗粒（secreto
8、ry granules）(直径约100 nm的囊泡)含有可溶性蛋白(电镜下呈暗色，也称大致密核心囊泡 large dense-core vesicles)膜特化区（Membrane differentiations)突触两侧膜结构 活化区（活化区（Active zone）椎体状，神经递质释放位点 突触后致密区（突触后致密区（postsynaptic density）含有受体使得细胞间信号转换成细胞内信号。化学突触的组分Types of synapsesPresynaptic axonPostsynaptic spinePostsynaptic densityActive zoneAstrocy
9、teCoated vesicleDense-core vesicleDouble-walled vesicleEndo.ReticulumMitochondrionPunctum adhaerensSynaptic cleftSynaptic vesicleTypes of synapsesDifferent types in of synapse in the CNS(CNS synapses)The sizes and shapes of CNS synapses also vary widelyAxodendritic,Axosomatic,axoaxonic,dendrodendrit
10、ic synapses.Types of synapsesChemical synapses as seen with EM(left)A fast excitatorysynapse in the CNS(right)A synapse in the PNS,with numerous dense-core vesiclesDCVAZMtPresynapticPostsynapticVSynaptic arrangements in the CNS.(a)An axodendritic synapse.(b)An axosomatic synapse.(c)An axoaxonic syna
11、pse.Types of synapsesVarious sizes of CNS synapses.Notice that larger synapses have more active zones.Types of synapsesTwo categories of CNS synaptic membrane differentiations.(a)A Grays type I synapse is asymmetrical and usually excitatory.(b)A Grays type II synapse is symmetrical and usually inhib
12、itory.Types of synapsesSynaptic junctions also exist outside the central nervous system.Axons of the autonomic nervous system innervate glands,smooth muscle,and the heart.Neuromuscular junctions occur between the axons of motor neurons of the spinal cord and skeletal muscle.NMJ has many of the struc
13、tural features of chemical synapses in the CNS.Neuromuscular synaptic transmission is fast and reliable.An AP in the motor axon always causes an AP in the muscle cell it innervates(What structural features for this reliability?)Most knowledge from the research on NMJ transmission.Types of synapsesTh
14、e neuromuscular junction.The postsynaptic membrane,known as the motor endplate,contains junctional folds with numerous neurotransmitter receptors.Types of synapsesPrinciples of chemical synaptic transmissionThere basic requirements for chemical synaptic transmission:p Synthesis and package into vesi
15、cles of neurotransmitter(NT);p Release of vesicle NT to cleft in response to a presynaptic AP;p Induction of an electrical or biochemical response to NT in the postsynaptic neuronp Clearance of NT from the synaptic cleft And,occur very rapidly to be useful for sensation,perception,and the control of
16、 movement.Principles of chemical synaptic transmissionNeurotransmitters（three chemical categories）g-氨基丁酸 乙酰胆碱 胆囊收缩素 谷氨酸 多巴胺 强腓肽 甘氨酸 肾上腺素 脑啡肽 组胺 N-乙酰门冬氨酰谷氨酸 去甲肾上腺素 神经肽Y 5-羟色胺 生长抑素 P物质 促甲状腺素释放激素 血管活性肠肽Neurotransmitters Three chemical categories Amine,amino acid,peptide Secretory granules and synaptic
17、vesicles Often co-exist in the same axon terminalsamine+peptideamino acid+peptide Different neurons release different neurotransmittersFast transmission;NMJ;Slow transmissionPrinciples of chemical synaptic transmissionRepresentative neurotransmitters(a)glutamate,GABA,and glycine.(b)acetylcholine and
18、 norepinephrine.(c)substance P.Principles of chemical synaptic transmissionPrinciples of chemical synaptic transmissionNeurotransmitter Synthesis and Storagep Amine and amino acid neurotransmitters:Enzymes are transported to the axon terminal and convert precursor molecules into neurotransmitter mol
19、ecules in the cytosol.Transporter proteins load the neurotransmitter into synaptic vesicles in the terminal,where they are stored.Glu,Gly vs GABA,the aminesp Peptides:A precursor peptide(a long peptide)synthesis in the rough ER in cell body.Then split in the Golgi apparatus to yield the active one.S
20、ecretory vesicles with the peptide bud off from the Golgi apparatus.The secretory granules are transported(axoplasmic)down the axon to the terminal where the peptide is stored.Principles of chemical synaptic transmissionp Transporters,proteins in the vesicle membrane,take up and concentrate the amin
21、o acid and amaine neurotransmitters inside the vesicle.Principles of chemical synaptic transmissionNeurotransmitter Releasep An action potential in the axon terminal depolarization of the terminal membrane voltage-gated calcium channels in the active zones to open（Ca2+i 0.0002 mM 0.1 mM）vesicles rel
22、ease（exocytosis）the contents to spill out into the synaptic cleftp The exocytosis occurs very rapidly within 0.2 msec of the Ca2+influx into the terminal.Why?p The mechanism by which Ca2+i stimulates exocytosis:Reserve pool of vesicles bound to the cytoskeleton Docking of vesicles to active zone SNA
23、RE protein complex,conformation altered by Ca2+i Endocytosis Recycled vesicle refilled with neurotransmitterPrinciples of chemical synaptic transmissionThe Release of Neurotransmitter by ExocytosisPrinciples of chemical synaptic transmission(a)This is a view of the extracellular surface of the activ
24、e zone of a neuromuscular junction in a frog.The particles are believed to be calcium channels.(b)In this view,the presynaptic terminal had been stimulated to release neurotransmitter.The exocytotic fusion pores are where synaptic vesicles have fused with the presynaptic membrane and released their
25、contents.A“receptors eye”view of neurotransmitter releasePrinciples of chemical synaptic transmissionSNAREs and vesicle fusion(Box 5.3)SNARE:SNAP ReceptorSNAP:Soluble NSF Attach ProteinNSF:N-ethylmaleimide-sensitive factor (N-乙基马来酰亚胺敏感的融合因子)Principles of chemical synaptic transmissionSecretory granu
26、les also release peptide neurotransmitters by exocytosis：p in a calcium-dependent fashionp typically not at the active zonesp requires high-frequency trains of AP and more calcium influx.p a leisurely process to taking 50 msec or more.Principles of chemical synaptic transmissionNeurotransmitter Rece
27、ptors and Effectorsp binding to specific receptor proteins in the postsynaptic density.p key in a lock,induce conformational changes in the receptor and lead to different functions.p More than 100 different receptors can be classified into two types:transmitter-gated ion channels and G-protein-coupl
28、ed receptors.Receptors Ion channels Receptorchannelsor Ionotropic receptors,or Ligand-gated ion channelsG-protein Coupled ReceptorsEnzyme linked receptors Nuclear receptors Voltage-gatedMechanically-gatedNon-gatedPrinciples of chemical synaptic transmissionTransmitter-gated ion channelsPrinciples of
29、 chemical synaptic transmissionTransmitter-Gated Ion Channelsp Membrane-spanning proteins consisting of four or five subunits to form a pore.p Closed to open,neurotransmitter,binds to specific sites,induces a conformational changep The functional consequence depends on which ions.The structure of an
30、 ACh-gated ion channelPrinciples of chemical synaptic transmissionIon selectivity of transmitter-gated channels and postsynaptic potential Channels permeable to Na+,Depolarization,to be excitatoryExcitatory postsynaptic potential(EPSP)Ach-or Glutamate-gated channelsPrinciples of chemical synaptic tr
31、ansmissionChannels permeable to Cl-,Hyperpolarization,to be inhibitoryInhibitory postsynaptic potential(IPSP)BABA-or Glycine-gated channelsPrinciples of chemical synaptic transmissionG-Protein-Coupled Receptors(GPCR)Fast chemical synaptic transmission is mediated by amino acid and amine neurotransmi
32、tters acting on transmitter-gated ion channels.However,all three types of neurotransmitter,acting on GPCR,can also have slower,longer-lasting,and much more diverse postsynaptic actions.This type of transmitter action involves three steps:Transmitters bind to receptors in the postsynaptic membrane.Th
33、e receptors activate G-proteins,free to move along the intracellular face of the postsynaptic membrane.The activated G-proteins activate“effector”proteins.Principles of chemical synaptic transmissionEffector proteinsp G-protein-gated ion channels in the membrane(left)p Enzymes that synthesize second
34、 messengers(right)Second messengers can activate additional enzymes in the cytosol that can regulate ion channel function and alter cellular metabolism.GPCR often referred to as metabotropic receptors.Principles of chemical synaptic transmissionp In the heart,a metabotropic ACh receptor is coupled b
35、y a G-protein to a potassium channel.It slows the rhythmic contractions of the heart by causing a slow hyperpolarization of the cardiac muscle cells.p In skeletal muscle,the receptor is an ACh-gated ion channel,permeable to Na+.ACh induces contraction by causing a rapid depolarization of the muscle
36、fibers.The same neurotransmitter can have different postsynaptic actions,depending on what receptors it binds to.Principles of chemical synaptic transmissionp Neurotransmitter receptors are also commonly found in the membrane of the presynaptic axon terminal.p Sensitive to the neurotransmitter,calle
37、d autoreceptors.p Typically,autoreceptors are GPCRp The common consequences of activating autoreceptors is inhibition of neurotransmitter release.This allows a presynaptic terminal to regulate itselfAutoreceptors Neurotransmitter Recovery and DegradationPrinciples of chemical synaptic transmissionNe
38、urotransmitter in the synaptic cleft must be cleared to allow another round of synaptic transmission.p Simple diffusion(For most of the amino acid and amine neurotransmitters)p Reuptake occurs by the action of specific transporter proteins located in the presynaptic membrane(once inside the cytosol,
39、enzymatically destroyed,or reloaded into synaptic vesicles)Neurotransmitter transporters also exist in the membranes of glia surrounding the synapse,which assist in such removal.p Enzymatic destruction in the cleft.Ach is removed at the NMJ by enzyme acetylcholinesterase,deposited in the cleft.Impor
40、tance of removal:desensitization(脱敏);nerve gasesNeuropharmacology Each of the steps of synaptic transmission is chemical,and therefore can be affected by specific drugs and toxins.Inhibitors:e.g.Nerve gases inhibite the enzyme AChE.Inhibitors of neurotransmitter receptors,called receptor antagonists
41、(e.g.Curare,an arrow-tip poison,binds tightly to the ACh receptors)Receptor agonists.e.g.nicotine,binds to,and activates,the ACh receptors in skeletal muscle and CNS.nicotinic ACh receptors(nAChR).Wrong neurotransmission is the root cause of many neurological and psychiatric disorders.Knowledge of n
42、europharmacology of synaptic transmission will be helpful for development of new and effective therapeutic drugs.Principles of chemical synaptic transmissionl Principles of synaptic integration The integration of EPSPs The contribution of dendritic properties Inhibition ModulationPrinciples Of Synap
43、tic IntegrationPrinciples Of Synaptic IntegrationThe postsynaptic neuron integrates thousands of synaptic inputs(complex ionic and chemical signals)and gives rise to a simple form of output:AP The transformation constitutes a neural computation.The brain performs billions of neural computations ever
44、y second.Synaptic integration is the process by which multiple synaptic potentials combine within one postsynaptic neuron.Principles Of Synaptic IntegrationThe Integration of EPSPs The opening of a single transmitter-gated channelA patch-clamp recording from a transmitter-gated ion channel.Ionic cur
45、rent passes through the channels when the channels are open.In the presence of neurotransmitter,they rapidly alternate between open and closed states.Patch Clamps Permit Measurement of Ion Movements through Single Channel(not only in a whole cell)Patch Clamp(膜片钳膜片钳)Different configurationsPrinciples
46、 Of Synaptic IntegrationPrinciples Of Synaptic IntegrationQuantal Analysis(量子分析量子分析)of EPSPs:a method of comparing the amplitudes of miniature and evoked postsynaptic potentials.The neurotransmitter content in a single synaptic vesicle.Spontaneous release w/o AP,one vesicle miniature EPSP(miniEPSP,m
47、EPSP)Multiple vesicle release w AP(evoked)EPSP(multiples of mEPSP)i.e.postsynaptic EPSPs at a given synapse are quantized;they are multiples of an indivisible unit,the quantum,that reflects the number of transmitter molecules in a single synaptic vesicle and the number of postsynaptic receptors avai
48、lable at the synapse.Principles Of Synaptic IntegrationThere is a big difference between excitatory transmission at NMJ and CNS synapses.Most neurons in CNS perform more sophisticated computations,requiring that many EPSPs add together to produce a significant postsynaptic depolarization.This is wha
49、t is meant by integration of EPSPs.EPSP summation is the simplest form of synaptic integration.Spatial summation is the adding together of EPSPs generated simultaneously at many different synapses on a dendrite.Temporal summation is the adding together of EPSPs generated at the same synapse if they
50、occur in rapid succession,within about 115 msec of one another.Principles Of Synaptic Integration(a)An AP triggers a small EPSP in a postsynaptic neuron.(b)Spatial summation:When two or more presynaptic inputs are active at the same time,their individual EPSPs add together.(c)Temporal summation:When
