Michael J. Fox Hollywood actor John Nash Nobel prize laureate 1994 Synaptic transmission Sompol Tapechum, M.D., Ph.D. Department of Physiology Faculty of Medicine Siriraj Hospital sisth@mahidol.ac.th www.ps.si.mahidol.ac.th Parkinson s disease Schizophrenia Objectives Before Botulinum Toxin After เม อจบบทเร ยน น กศ กษาสามารถ 1. บอกความหมาย, โครงสร าง และชน ดของ Synapse ได 2. บอกข อแตกต างและความส าค ญของ Electrical และ Chemical Synapses ได 3. อธ บายกลไกการหล งสารส อประสาทท เก ดข นท Chemical Synapse ได 4. อธ บายกลไกการออกฤทธ ของสารส อประสาทท postsynaptic membrane ได 5. อธ บายกลไกการเก ด Excitatory and Inhibitory Postsynaptic Potential (EPSP และ IPSP) 6. บอกข อแตกต างและความส าค ญของ Fast และ Slow Synaptic transmission ได 7. อธ บายกลไกการส นส ด Synaptic transmission ใน chemical synapses ได 8. บอกป จจ ยท ม ผลต อการหล งและการออกฤทธ ของสารส อประสาทได Neuron Synapse Neuron (Am) Neurone (En) Human brain contains 100 billion (10 11 ) neurons Neurons serve as the functional signaling units of the nervous system and that neurons connect to one another in precise ways. : The Neuron Doctrine (Santiago Ramon y Cajal,1894) Synapse (Gr. Synapsis = union or association) Specialized zone of contact at which one neuron communicates with another Neuronal Synapses Neuro-effector Synapses: Neuromuscular junction
Structure of neuronal synapse Sites of neuronal synapses Axodendritic Axosomatic Axoaxonic Convergence VS Divergence 1. Convergence Communication across synapse 2. Divergence Action potential propagation Synaptic transmission Chemical synapse Electrical synapse Chemical synapse Structure of chemical synapses (1) Communication using chemical messengers Neurotransmitters across synaptic cleft Presynaptic terminal Synaptic cleft (20 nm) Pre Post Postsynaptic membrane Unidirectional or Orthodromic conduction
Structure of chemical synapses (2) mitochondria Active Zone Postsynaptic density Criteria for neurotransmitter 1. It is synthesized in the neuron. 2. It is present in the presynaptic terminal. 3. It is released by a neuron when the the neuron is stimulated. 4. After released, it exerts a defined action on postsynaptic neuron or effector organ. 5. A specific mechanism exists for removing it from the site of action. 6. Exogenous administration mimics the endogenously released transmitter exactly. Classes of neurotransmitters Small molecule neurotransmitters or classical neurotransmitter synthesized in presynaptic terminal stored in small clear vesicles Acetylcholine Biogenic amines: dopamine, adrenaline, noradrenaline, setotonin, histamine Amino acids: glutamate, glycine, GABA Purines: adenosine, ATP Neuroactive peptides synthesized from mrna in soma of presynaptic neurons stored in large dense-cored vesicles Substance P, VIP, Somatostatin, cholycystokinin, enkephalin Neurotransmitter synthesis Neurotransmitters are synthesized in presynaptic neurons and stored in synaptic vesicles Acetylcholine: Acetyl CoA + Choline Norepinephrine: Choline acetyl transferase Hydroxylation 1. Tyrosine DOPA 2. DOPA Decarboxylation Dopamine Acetylcholine Hydroxylation 3. Dopamine Norepinephrine (in synaptic vesicles) Acetylcholine synthesis Neurotransmitter release AcCoA postsynaptic potential ATP Proton transporter H + ADP NVP action potential Vesicular ACh transporter H + ACh Vesamicol Choline+AcCoA ACh+HSCoA ChAT voltage-gated Ca 2+ channels Ca 2+ -dependent process Vesicle fusion exocytosis Vesicle mobilization exocytosis needs energy (ATP) postsynaptic receptors
Synaptic delay Postsynaptic potential Excitatory postsynaptic potential (EPSP) Na + influx Synaptic delay 0.3-5 ms Inhibitory postsynaptic potential (IPSP) Cl - influx K + efflux Mechanism of end-plate potential (EPP) Properties of postsynaptic potential acetylcholine bind nicotinic receptors Opening of ligand-gated channels Na + influx and K + efflux driving force for Na + =-(E m -E Na ) driving force for K + = (E m -E K ) At equilibrium -(E m -E Na )=(E m -E K ) E m = (E Na + E K )/2 E Na =50mV and E K =-90mV ==> EPP =-20mV End-plate potential (EPP) Local potential Electrotonic conduction Graded response Can be summated Can be EPSP or IPSP Summation of PSP (1) Spatial summation When activity is present in more than one synaptic knob at the same time Summation of PSP (2) Temporal summation When repeated afferent stimuli cause new PSPs before previous PSPs have decayed Spatial summation
Neural encoding Frequency coding larger EPSP ==> higher frequency Postsynaptic effects Types of Neurotransmitters: Glutamate stimulate GABA inhibit Types of Postsynaptic receptors Acetylcholine: Nicotinic and Muscarinic receptors (M1-M5) Skeletal Muscle Nicotinic Contraction Smooth Muscle M1 Contraction Cardiac pacemaker M2 bradycardia Postsynaptic receptors (1) Ionoropic receptor Ligand-gated channel: opening or closing ion channel Fast action and inactivation nicotinic acetylcholine receptor Glutamate receptor: NMDA, AMPA, Kainate GABA A Postsynaptic receptors (2) Metabotropic receptor G protein-coupled receptor Production of second messenger molecules eg. camp muscarinic acetylcholine receptor adrenergic receptor dopaminergic receptor metabotropic glutamic receptor serotonin receptor Fast VS Slow synaptic transmission Threshold Fast synaptic transmission Direct effect on action potential influx of Na + Slow synaptic transmission Modulate RMP and membrane excitability Opening or closing of K + channel Termination of neurotransmitter effects Reuptake Dopamine, noradrenaline Enzymatic degradation Acetylcholine acetylcholine esterase Catecholamine Monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT) Diffuse away
Acetylcholine: release, inactivation and choline uptake Psychostimulants: Cocaine and amphetamine Cocaine Block reuptake Amphetamine Competitive inhibitor for reuptake Cocaine blocks dopamine transporter Glial recycle of neurotransmitter Factors affecting synaptic transmission Synaptic plasticity Synaptic conduction can be strengthened or weakened on the basis of pass experience By changing of structure and/or functions 1. Factors affecting Ca 2+ concentration Resting membrane potential Presynaptic facilitation: Potassium channel blocking Presynaptic inhibition: Calcium channel blocking, Membrane hyperpolarization Duration of action potential: Potassium channel blocking Frequency of action potential: Post tetanic potentiation 2. Factors affecting the synaptic vesicle pool Protein kinase C 3. Factors affecting Ca 2+ sensitivity of release machinery Protein kinase C Electrical synapse Communication using ionic current through gap junction channels
Gap junction channel Electrical synaptic transmission Gap Junction=2 Connexons Connexon made of 6 connexins Electrical VS Chemical synapse Property Distance between Membranes Cytoplasmic continuity? Structural Unit(s) Electrical Synapse 3.5 nm Yes Gap-junction channel Chemical Synapse 20-40 nm No Many (vesicles, docking/fusion proteins, and postsynaptic receptors) Advantages of chemical synapses 1. Unidirectional 2. Integration of signals 3. Modulation of synaptic transmission Transmitter Ionic current Chemical transmitter Transmission Delay Transmission Direction No Can be bi-directional Yes (usually 1-5 msec) Unidirectional (Orthodromic conduction) Post tetanic potentiation Presynaptic facilitation Conclusion 1. Synaptic transmission can be electrical or chemical. 2. Chemical synaptic transmission is major communication in nervous system. 3. Chemical synapses are plastic, ie can be modulated by several factors 4. Effects of neurotransmitters on postsynaptic cells depend on types of neurotransmitters and postsynaptic receptors.