Neurotransmitters

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1 神经元间的功能联系 -- 突触传递 (synapse transmission) Albert Cheung Hoi Yu 于常海北京大学神经科学研究所 Neuroscience Research Institute Peking University Department of Neurobiology Peking University Health Science Center

2 Synaptic Transmission ( 经典的突触传递 ) Synapse 最初是指细胞与细胞之间相接处并传递信息的部位因此, 广义的突触也包括了神经 - 肌接头 1 含义 : 具体到神经系统, 突触是指神经元之间相互接触并传递信息的部位 2 组成 : 由一个神经元的轴突然袭击与其它神经元的胞体或突起形成 3 结构 : 电镜下可见突触接触处各有膜分开轴突末梢的分支膨大构成突触小体, 突触小体膜称为突触前膜与前膜相对应的胞体或突起膜称为突触后膜, 两膜之间的间隙称为突触间隙

3 Chemical Synapse 结构特点 : 突触前后膜比一般的神经元膜增厚约 7nm 间隙较宽, 约 20~39nm, 其间有粘多糖和糖蛋白突触小体内有许多的线粒体和囊泡 ( 囊泡内含递质 ) 突触后膜上有相应的受体

4 Ca+ 在突触传递中的作用 : Ca+ 在突触传递中的作用 : At a chemical synapse, neurons transmit information across a cleft.

5 Classification of Synapses Morphology : axodendritic axonsomatic axoaxonic 其他 :D-D D-S D-A S-D S-S S-A serial synapse ( 串联性突触 ) reciprocal synapse ( 交互性突触 ) mixed synapse ( 混合性突触 ) Serial Mixed Reciprocal

6 Microstructure of Chemical Synapse ( 突触的微细结构 ) presynaptic membrane ( 突触前膜 ) 三类突触小泡 (synaptic vesicle), mitochondria, 其他 synaptic cleft ( 突触间隙 ) 宽 20~40 nm, 与细胞外液相通 postsynaptic membrane ( 突触后膜 ) active zone ( 激活区 ) receptor ( 受体 )

7 Electrical Synapse Chemical Synapse

8 Distinguishing Properties of Electrical and Chemical Synapses Types of synapse Cytoplasmic continuity Distance Ultrastructural component Agent of transmission Synaptic delay Direction of transmission Electrical 3.5 nm Yes Gap-junction channel Ion current Virtually absent Usually bidirectional Chemical nm No Presynaptic vesicle and active zone; postsynaptic receptors Chemical transmitters Significant: at least 0.3 ms; usually 1-5 ms or longer Unidirectional

9 Non-directed synaptic transmission ( 非定向突触传递 ) 结构基础 : 曲张体 (varicosity) 特点 : 无前膜与后膜之分, 支配为 1 : n 距效应器远 (>20 nm), 费时 (>1 s), 不一定产生效应分布 : 神经 - 平滑肌和心肌接头, 中枢单胺类纤维

10 Two Categories of CNS Synaptic Membrane Differentiations A Gray s type 1 synapse is asymmetrical and usually excitatory A Gray type II synapse is symmetrical and usually inhibitory.

11 Various sizes of CNS synapses note the large size has more active zones.

12 7. 突触的可塑性 (plasticity) 强直后增强 (post tetanic potentiation) 习惯化 (habituation) 敏感化 (sensitization) 长时程增强 (long-term potentiation, LTP) 长时程抑制 (long-term depression, LTD)

All known neurotransmitter receptors can be divided into two groups according to the way in which receptor and effector functions are coupled. A.

13 All known neurotransmitter receptors can be divided into two groups according to the way in which receptor and effector functions are coupled. A. Ionotropic receptors directly gate ion channels as part of a single macromolecule that also forms the ion channel. The receptor, located on the extracellular side, and the ion channel pore, embedded in the cell membrane, are formed within the same protein. B. Receptors that indirectly gate ion channels fall into two families. 1.Metabotropic G protein-coupled receptors activate ion channels and other substrates indirectly by activating a GTP-binding protein that often engages a secondmessenger cascade. 2.Receptor tyrosine kinases modulate the activity of ion channels indirectly through a cascade of protein phosphorylation reactions, beginning with autophosphorylation of the kinase itself on tyrosine residues.

14 Modulatory synaptic actions involving second messengers occur at three sites. A. Synaptic action at presynaptic terminals can activate second messengers that regulate presynaptic K+ and Ca2+ channels, thus regulating transmitter release and the size of the postsynaptic potential. B. Synaptic action at the postsynaptic membrane can activate second messengers that alter the size of fast postsynaptic potentials by modulating ionotropic receptors. C. Second messengers can affect the function of resting and voltage-

16 Post-synaptic Potential(PSP, 突触后电位 ) 1. excitatory post-synaptic potential (EPSP, 兴奋性突触后电位 ) 2. inhibitory post-synaptic potential(ipsp. 抑制性突触后电位 )

17 兴奋性突触后电位 (excitatory ~, EPSP) 性质 : 后膜去极化, 局部电位实例 : 肌梭传入 - 脊髓运动神经元突触机制 : 某种兴奋性递质突触后膜受体 Na + Ca 2+ 通道开放 Na + Ca 2+ 内流局部后膜去极化抑制性突触后电位 (inhibitory ~, IPSP) 性质 : 后膜超极化, 局部电位实例 : 肌梭传入侧支 - 脊髓运动神经元联系机制 : 某种抑制性递质突触后膜受体 Cl 通道开放 ( 也可有 K + 通道开放 Na + Ca 2+ 通道关闭 ) Cl 内流 ( 也可能有 K + 外流 ) 局部后膜超极化

18 EPSP Summation: a.a presynaptic action potential triggers a small EPSP in a post-synaptic neurons. b.spatial summation of EPSPs: when two or more presynaptic inputs are active at the same time, their individual EPSP s add together. c.temporal summation of EPSPs: when the same presynaptic fibers fires action potentials in quick succession, the individual EPSPs add together.

19 Shunting Inhibition A neurons receiving one excitatory and one inhibitory input. 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.

20 A high rate of stimulation of the presynaptic neuron produces a gradual increase in the amplitude of the postsynaptic potentials. This enhancement in the strength of the synapse represents storage of information about previous activity, an elementary form of memory. The time scale of the experimental record here has been compressed (each pre-synaptic and postsynaptic potential appears as a simple line indicating its amplitude). To establish a baseline (control), the presynaptic neuron is stimulated at a rate of 1 per second, producing a postsynaptic potential of about 1 mv. The presynaptic neuron is then stimulated for several seconds at a higher rate of 5 per second. During this tetanic stimulation the postsynaptic potential increases in size, a phenomenon known as potentiation. After several seconds of stimulation the presynaptic neuron is returned to the control rate of firing (1 per second). However, the postsynaptic potentials remain enhanced for minutes, and in some cells for several hours. This persistent increase is called posttetanic potentiation.

21 Action Potential 21

22 AP 在突触后神经元的产生 nepsp+mipsp( 总和 ) 膜电位去极化 ( 70 mv 52 mv) 阈电位 AP 首先产生 AP 的部位轴突始段始段较细小, 跨膜电流密度较大始段膜上电压门控 Na + 通道密度较大然后传遍整个细胞膜沿轴突末梢 ; 逆向胞体

23 nerve impulse ( 神经冲动 ) 的概念神经纤维兴奋传导依靠局部电流而完成 conduction ( 兴奋传导 ) 的特征 integrality ( 完整性 ) isolated propagation ( 绝缘性 ) bidirectional propagation ( 双向性 ) indefatigability ( 相对不疲劳性 )

24 Function 功能 24

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27 What is Neurotransmitter( 神经递质 )? Chemicals move across synapse for communication of information Released from one neuron (the presynaptic nerve terminal) Accepted by the next neuron at a specialized site (the postsynaptic receptor) Activated a receptor site - depolarization (an excitatory postsynaptic potential) or hyperpolarization (an inhibitory postsynaptic potential) made in the cell body of the neuron

28 Neurotransmitter Criteria 1. The chemical must be produced within a neuron. 2. The chemical must be found within a neuron. 3. When a neuron is stimulated (depolarized), a neuron must release the chemical. 4. When a chemical is released, it must act on a postsynaptic receptor and cause a biological effect. 5. After a chemical is released, it must be inactivated. Inactivation can be through a reuptake mechanism or by an enzyme that stops the action of the chemical. 6. If the chemical is applied on the post-synaptic membrane, it should have the same effect as when it is released by a neuron.

29 Termination of Neurotransmitter Action 1. Diffusion: the neurotransmitter drifts away, out of the synaptic cleft where it can no longer act on a receptor. 2. Enzymatic degradation (deactivation): a specific enzyme changes the structure of the neurotransmitter so it is not recognized by the receptor. For example, acetylcholinesterase is the enzyme that breaks acetylcholine into choline and acetate. 3. Reuptake: the whole neurotransmitter molecule is taken back into the axon terminal that released it. This is a common way the action of norepinephrine, dopamine and serotonin is stopped. These neurotransmitters are removed from the synaptic cleft so they cannot bind to receptors.

32 List of some of Neurotransmitter 1. Small Molecule Neurotransmitter Substances Acetylcholine (ACh); Dopamine (DA); Norepinephrine (NE); Serotonin (5-HT); Histamine 2. Amino Acids Gamma-aminobutyric acid (GABA); Glycine; Glutamate; Aspartate 3. Neuroactive Peptides - partial list!! Bradykinin; beta-endorphin; calcitonin; cholecystokinin; enkephalin; dynorphin; insulin; gastrin; substance P; glucagon; secretin; vasopressin; oxytocin, etc. 4. Gases Nitric oxide (NO); carbon monoxide (CO)

35 Receptor ( 受体 ) 概念 : 分布于细胞膜或细胞内与某些物质特异结合, 生产效应化学本质 : 带糖链的跨膜蛋白质激动剂拮抗剂和配体的概念亚型 : 使效应多样化突触前受体 (presynaptic receptor)

38 Three physical models for the opening and closing of ion channels. A. A localized conformational change occurs in one region of the channel. B. A generalized structural change occurs along the length of the channel. C. A blocking particle swings into and out of the channel mouth.

39 Several types of stimuli control the opening and closing of ion channels. A. Ligand-gated channels open when the ligand binds to its receptor. The energy from ligand binding drives the channel toward an open state. B. Protein phosphorylation and dephosphorylation regulate the opening and closing of some channels. The energy for channel opening comes from the transfer of the high-energy phosphate, Pi. C. Changes in membrane voltage can open and close some channels. The energy for channel gating comes from a change in the electrical potential difference across the membrane, which causes a conformational change by acting on a component of the channel that has a net charge. D. Channels can be activated by stretch or pressure. The energy for gating may come from mechanical forces that are passed to the channel through the cytoskeleton.

40 2 神经纤维 Nerve Fiber (NF) 轴索 (neurite, 中央部分 ) 内含半流动状神经浆线粒体微管和微丝等轴膜 : 施万细胞包绕 (myelinated) 无施万细胞包绕 (non-myelinated) 40

41 Myelinated Nerve Fiber Classification 神经纤维的分类 Afferent Fiber Groups Muscle nerve Cutaneous nerve Fiber diameter Conducti on velocity( m/s) Large I (a,b) Aα Small II Aβ,γ Smallest III Aδ, Β Unmyelina ted IV C

42 神经纤维分类 (classification) 类型功能直径 (µm) 速度 (m/s) 相当于 A α 本体感觉, 躯体运动 12~22 70~120 I a I b A β 触 - 压觉 5~12 30~70 II A γ 支配梭内肌 ( 使收缩 ) 3~6 15~30 A δ 痛温触 - 压觉 2~5 12~30 III B 自主神经节前纤维 < 3 3~15 sc 交感节后纤维 0.3~ ~2.3 IV drc 痛温触 - 压觉 0.4~ ~2.0 IV

43 carry Proprioception Tou ch Pain Pain/temp. information Temperature / itch 43

44 How fast does information travel in the nervous system? Information travels at different speeds within different types of nerve. Transmission can be as slow as 0.5 m/sec or as fast as 120 m/sec. Travelling at 120 m/sec is the same as going 268 miles/hr!!! 44

45 affecting factors ( 影响兴奋传导速度的因素 ) diameter ( 直径 ) myelin sheath ( 有无髓鞘 ) thickness ( 髓鞘厚度 ) temperature ( 温度 ) significance ( 测量兴奋传导速度的意义 ) 有助于诊断神经纤维疾患有助于估计神经损伤的预后

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47 Organization of Neuronal Pools

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49 Axonal Transport Systems Axonal transport : intracellular communication Bidirectional mechanism : anterograde transport retrograde transport Classified by transport rates : slow transport system (0.2 to 1 mm/day) fast transport system (200 to 400 mm/day) 49

50 Major Rate Components of Axonal Transport Component Fast transport Rate (mm/day) Structure and composition Anterograde Small vesiculotubular structures, neurotransmitters; Mitochondria Mitochondria membrane proteins and lipids Retrograde Lysosomal vesicles and enzymes Slow transport SCb 2-8 SCa Microfilaments, metabolic enzymes, clathrin complex Neurofilaments and microtubules 50

51 营养作用通过轴浆流动未梢释放某些调节性物质改变组织内在代谢活动, 影响其支配组织的结构和功能, 与神经冲动无关此外, 被支配的组织和胶质细胞也能产生支持神经原的神经营养因子 (neurotrophin,nt), 其本质为蛋白质, 已分离出的 NT 有 : 神经生长因子 (NGF) 神经营样因子 -3(NT-3) 神经营养因子 4/5(NT-4/5) 和脑原性神经营养因子 (BDNF) 等神经营养因子的运输 : NT 作用于神经末稍的特异受体被末梢摄取逆向轴浆运输胞体在神经末稍发现多种 NT 的受体 :Trk A Trk B 和 Trk C 51

Chapter 8

Chapter 8 Consciousness, The Brain and Behavior 識行 I. States of Consciousness 識狀 (I) Electroencephalogram The electroencephalogram provides one means of defining the states of consciousness. 了識狀 Electric