突触传递突触传递 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) 概论 Introduction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）Introduction十九世纪末，人们已认识到信息从一个神 Ø 突触 Synapse (1897 Charles Sherrington)Ø 突触传递 – two hypothesis Argued for a century on its physical nature.Ø 电突触 - Electrical synapse (Proven in 1959 by E. Furshpan and D. Potter in crayfish)Ø 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Ø是一项重要的研究主题Introduction 突触 SynapseIntroduction IntroductionOtto 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。
IntroductionOtto Loewi (1873-1 Types of synapses 突触是神经元特化的连接，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1–2 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 突触是神经 Types of synapses 一个gap junction将两个细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 一个gap jun Types of synapses电突触的功能特征：Ø双向等效通过Ø电耦合Ø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电突触的功能特征： Types of synapses电突触也存在于脊椎动物的神经系统Ø中枢神经系统各部分均有Ø在电耦合的神经元间，突触前的动作电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)Ø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Ø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;). Ø见教科书，Box 5-2 by Michael V. L. BennettTypes of synapses电突触也存在于脊椎动物的神 Types of synapses 电突触： (a) 缝隙连接（gap junction）偶联了二个神经元构成一个电突触；(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 电突触： Types of synapses化学突触（化学突触（Chemical synapses））Ø一般概念: 突触间隙（synaptic cleft）） (20–50 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（secretory 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Types of synapses化学突触（Chemical 化学突触的组分Types of synapses化学突触的组分Types of synapses Presynaptic axonPostsynaptic spinePostsynaptic densityActive zoneAstrocyteCoated vesicleDense-core vesicleDouble-walled vesicleEndo. ReticulumMitochondrionPunctum adhaerensSynaptic cleftSynaptic vesicleTypes of synapsesPresynaptic axonPostsynaptic s Different types in of synapse in the CNS (CNS synapses) The sizes and shapes of CNS synapses also vary widelyAxodendritic, Axosomatic, axoaxonic, dendrodendritic 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 vesiclesDCVAZMtPresynapticPostsynapticVDifferent types in of synapse Synaptic arrangements in the CNS. (a) An axodendritic synapse. (b) An axosomatic synapse. (c) An axoaxonic synapse.Types of synapsesSynaptic arrangements in the C Various sizes of CNS synapses. Notice that larger synapses have more active zones.Types of synapsesVarious sizes of CNS synapses. Two categories of CNS synaptic membrane differentiations. (a) A Gray’s type I synapse is asymmetrical and usually excitatory.(b) A Gray’s type II synapse is symmetrical and usually inhibitory.Types of synapsesTwo categories of CNS synaptic Synaptic junctions also exist outside the central nervous system. ØAxons of the autonomic nervous system innervate glands, smooth muscle, and the heart. ØNeuromuscular junctions occur between the axons of motor neurons of the spinal cord and skeletal muscle. NMJ has many of the structural features of chemical synapses in the CNS.ØNeuromuscular 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?)ØMost knowledge from the research on NMJ transmission.Types of synapsesSynaptic junctions also exist The neuromuscular junction. The postsynaptic membrane, known as the motor endplate, contains junctional folds with numerous neurotransmitter receptors.Types of synapsesThe neuromuscular junction. Th Principles of chemical synaptic transmissionThere basic requirements for chemical synaptic transmission:pSynthesis and package into vesicles of neurotransmitter (NT); pRelease of vesicle NT to cleft in response to a presynaptic AP; pInduction of an electrical or biochemical response to NT in the postsynaptic neuronpClearance of NT from the synaptic cleft And, occur very rapidly to be useful for sensation, perception, and the control of movement.Principles of chemical synapti 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Principles of chemical synapti Neurotransmitters ü Three chemical categories Amine, amino acid, peptideü Secretory granules and synaptic vesiclesü Often co-exist in the same axon terminalsamine + peptideamino acid + peptideü Different neurons release different neurotransmittersFast transmission; NMJ; Slow transmissionPrinciples of chemical synaptic transmissionNeurotransmitters Principles o Representative neurotransmitters(a)glutamate, GABA, and glycine. (b)acetylcholine and norepinephrine.(c) substance P. Principles of chemical synaptic transmissionRepresentative neurotransmitte Principles of chemical synaptic transmissionNeurotransmitter Synthesis and StoragepAmine and amino acid neurotransmitters: ➀ Enzymes are transported to the axon terminal and convert precursor molecules into neurotransmitter molecules in the cytosol. ➁ Transporter proteins load the neurotransmitter into synaptic vesicles in the terminal, where they are stored. Glu, Gly vs GABA, the aminespPeptides: ➀ A precursor peptide (a long peptide) synthesis in the rough ER in cell body. ➁ Then split in the Golgi apparatus to yield the active one. ➂ Secretory vesicles with the peptide bud off from the Golgi apparatus. ➃ The secretory granules are transported (axoplasmic) down the axon to the terminal where the peptide is stored. Principles of chemical synapti Principles of chemical synaptic transmissionpTransporters, proteins in the vesicle membrane, take up and concentrate the amino acid and amaine neurotransmitters inside the vesicle.Principles of chemical synapti 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 release（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? pThe mechanism by which [Ca2+] i stimulates exocytosis: Reserve pool of vesicles bound to the cytoskeleton Docking of vesicles to active zone SNARE protein complex, conformation altered by ↑[Ca2+]i Endocytosis Recycled vesicle refilled with neurotransmitterPrinciples of chemical synapti Principles of chemical synaptic transmissionThe Release of Neurotransmitter by ExocytosisPrinciples of chemical synapti Principles of chemical synaptic transmission(a)This is a view of the extracellular surface of the active 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 contents.A “receptor’s eye” view of neurotransmitter releasePrinciples of chemical synapti Principles 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 synapti Principles of chemical synaptic transmissionSecretory granules 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 synapti Principles of chemical synaptic transmissionNeurotransmitter Receptors 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-coupled receptors.Principles of chemical synapti 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 channelsReceptors Ion chann Principles of chemical synaptic transmissionTransmitter-Gated Ion ChannelspMembrane-spanning proteins consisting of four or five subunits to form a pore.pClosed to open, neurotransmitter, binds to specific sites, induces a conformational changepThe functional consequence depends on which ions.The structure of an ACh-gated ion channelPrinciples of chemical synapti Principles 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 synapti Principles of chemical synaptic transmissionChannels permeable to Cl-, Hyperpolarization, to be inhibitoryInhibitory postsynaptic potential (IPSP)BABA- or Glycine-gated channelsPrinciples of chemical synapti Principles of chemical synaptic transmissionG-Protein-Coupled Receptors (GPCR)Fast chemical synaptic transmission is mediated by amino acid and amine neurotransmitters 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:① Transmitters bind to receptors in the postsynaptic membrane.② The receptors activate G-proteins, free to move along the intracellular face of the postsynaptic membrane.③ The activated G-proteins activate “effector” proteins.Principles of chemical synapti Principles of chemical synaptic transmissionEffector proteinsp G-protein-gated ion channels in the membrane (left)p Enzymes that synthesize second 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 synapti Principles of chemical synaptic transmissionpIn the heart, a metabotropic ACh receptor is coupled by 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. pIn skeletal muscle, the receptor is an ACh-gated ion channel, permeable to Na+. ACh induces contraction by causing a rapid depolarization of the muscle fibers. The same neurotransmitter can have different postsynaptic actions, depending on what receptors it binds to. Principles of chemical synapti Principles of chemical synaptic transmissionp Neurotransmitter receptors are also commonly found in the membrane of the presynaptic axon terminal.p Sensitive to the neurotransmitter, called 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 Principles of chemical synapti Neurotransmitter Recovery and DegradationPrinciples of chemical synaptic transmissionNeurotransmitter 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, enzymatically destroyed, or reloaded into synaptic vesicles) Neurotransmitter transporters also exist in the membranes of glia surrounding the synapse, which assist in such removal.pEnzymatic destruction in the cleft. Ach is removed at the NMJ by enzyme acetylcholinesterase, deposited in the cleft.Importance of removal: desensitization (脱敏); nerve gasesNeurotransmitter Recovery and Neuropharmacology 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 (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 neuropharmacology of synaptic transmission will be helpful for development of new and effective therapeutic drugs.Principles of chemical synaptic transmissionNeuropharmacologyPrinciples of lPrinciples of synaptic integration The integration of EPSPs The contribution of dendritic properties Inhibition ModulationPrinciples Of Synaptic IntegrationPrinciples of synaptic integra Principles 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 every second.Synaptic integration is the process by which multiple synaptic potentials combine within one postsynaptic neuron. Principles Of Synaptic Integra 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 current passes through the channels when the channels are open. In the presence of neurotransmitter, they rapidly alternate between open and closed states.Principles Of Synaptic Integra 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 Of Synaptic IntegrationPatch Clamps Permit Measuremen Principles 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, mEPSP)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 available at the synapse.Principles Of Synaptic Integra 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 what 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 occur in rapid succession, within about 1–15 msec of one another.Principles Of Synaptic Integra 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 the same presynaptic fiber fires APs in quick succession, the individual EPSPs add together.Principles Of Synaptic Integra Principles Of Synaptic IntegrationThe Contribution of Dendritic Properties to Synaptic IntegrationThe current of synaptic contact must spread down the dendrite and the soma, and cause the membrane of the spike-initiation zone to be depolarized beyond threshold, before an AP can be generated. The effectiveness of an excitatory synapse in triggering an AP, therefore, depends on how far the synapse is from the spike-initiation zone and on the properties of the dendritic membrane.Principles Of Synaptic Integra Principles Of Synaptic IntegrationDendritic Cable Properties:To simplify, let’s assume that dendrites function as cylindrical cables that are electrically passive; that is, lacking voltage-gated ion channels (in contrast, of course, with axons). Imagine that the current at a synapse is like turning on the water that will flow down a leaky garden hose (the dendrite). Similarly, two paths that synaptic current can take: One is down the inside of the dendrite; the other is across the dendritic membrane. At some distance from the site of current influx, the EPSP amplitude may approachzero because of the dissipation of the currentacross the membrane.Principles Of Synaptic Integra Principles Of Synaptic IntegrationTo simplify the mathematics, we assume the dendrite is infinitely long, unbranched, and uniform in diameter. The amount of depolarization falls off exponentially with increasing distance: Vx=V0/e x/λwhen x=λ, then Vx=V0/e. Put another way, Vλ=0.37 (V0). This distance λ, where the depolarization is 37% of that at the origin, is called the dendritic length constant. (Remember that this analysis is an oversimplification) . Principles Of Synaptic Integra Principles Of Synaptic Integration(a)The depolarization measured at a distance from the site of current injection is smaller than that measured right under it. (b)A plot of membrane depolarization as a function of distance along the dendrite.Decreasing depolarization as a function of distance along a long dendritic cablePrinciples Of Synaptic Integra Principles Of Synaptic IntegrationThe length constant is an index of how far depolarization can spread down a dendrite or axon. The longer the length constant, the more likely it is that EPSPs generated at distant synapses will depolarize the membrane at the axon hillock（轴丘）. λ depends on two factors: (1)the internal resistance (ri); and (2) the membrane resistance (rm). ri depends only on the diameter of the dendrite and the electrical properties of the cytoplasm (relatively constant in a mature neuron) rm, depends on the number of open ion channels, which changes from moment to moment depending on what other synapses are active. The dendritic length constant, therefore, is not constant at all! Principles Of Synaptic Integra Principles Of Synaptic IntegrationExcitable Dendrites. p Assumption: The dendrite’s membrane is electrically passive. The dendrites of spinal motor neurons are very close to passive. However, many other neuronal dendrites are decidedly not passive. p The voltage-gated channels in dendrites can act as important amplifiers of small EPSPs generated far out on dendrites. p Paradoxically, in some cells dendritic sodium channels may also serve to carry electrical signals in the other direction—from the soma outward along dendrites. Principles Of Synaptic Integra Principles Of Synaptic IntegrationA cortical pyramidal neuron with a long apical dendrite that has voltage-gated ion channelsPrinciples Of Synaptic Integra Principles Of Synaptic IntegrationInhibitionEPSP → AP output depends on:Øthe number of coactive excitatory synapsesØthe distance the synapse is from the spike-initiation zoneØthe properties of the dendritic membranePlus:Øinhibitory synapses that take the membrane potential away from action potential threshold, and exert a powerful control over a neuron’s output .Principles Of Synaptic Integra Principles Of Synaptic IntegrationIPSPs and Shunting Inhibition (分流抑制分流抑制)pThe postsynaptic inhibitory receptors are GABA or glycine-gated ion channels that they only allow Cl- to pass through their channels.pOpening of the chloride channel brings the membrane potential toward the chloride equilibrium potential, ECl-, about - 65 mV. So, whether its activation causes a hyperpolarizing IPSP or not depend on the resting membrane potential.pIf there is no visible IPSP, is the neuron really inhibited? The answer is yes. p Shunting inhibition (分流抑制分流抑制). The actual physical basis of shunting inhibition is the inward movement of negatively charged chloride ions, which is formally equivalent to outward positive current flow. p Thus, inhibitory synapses also contribute to synaptic integrationPrinciples Of Synaptic Integra Principles Of Synaptic Integration(a)Stimulation of the excitatory input causes inward postsynaptic current that spreads to the soma, where it can be recorded as an EPSP. (b)When the inhibitory and excitatory inputs are stimulated together, the depolarizing current leaks out before it reaches the soma.Shunting inhibition. Principles Of Synaptic Integra Principles Of Synaptic IntegrationThe Geometry of Excitatory and Inhibitory SynapsesInhibitory synapses (GABA or glycine), Gray’s type II. Excitatory synapses (glutamate), Gray’s type IInhibitory synapses on many neurons are found clustered on the soma and near the axon hillock.Principles Of Synaptic Integra Principles Of Synaptic IntegrationModulation (调制调制)In addition to synaptic transmitter-gated channels, there are many synapses with G-protein-coupled neurotransmitter receptors that do not directly evoke EPSPs and IPSPs, but instead modifies the effectiveness of EPSPs generated by other synapses. This is called modulation. e.g. norepinephrine β receptor. The binding of norepinephrine (NE) to the receptor triggers a cascade of biochemical events within the cell to produce the second messager cAMPPrinciples Of Synaptic Integra Principles Of Synaptic IntegrationModulation by the NE receptor. ➀ The binding of NE to the receptor activates a G-protein in the membrane. ➁ The G-protein activates the enzyme adenylyl cyclase. ➂ Adenylyl cyclase converts ATP into the second messenger cAMP. ➃ cAMP activates a protein kinase. ➄ The protein kinase causes a potassium channel to close by attaching a phosphate group to it.Principles Of Synaptic Integra Principles Of Synaptic Integrationdecreasing the K+ conductance increases the dendritic membrane resistance and therefore increases the length constant λ. Distant or weak excitatory synapses will become more effective in depolarizing the spike-initiation zone beyond threshold. i.e. the cell becomes more excitable.It is why excitability of a neuron is increased when NE is released presynaptically.END请好好思考讨论教材上的复习思考题！请好好思考讨论教材上的复习思考题！Principles Of Synaptic Integra 。