Synaptic Transmission BIO 417 Chapter 5 PDF

SYNAPTIC TRANSMISSION Chapter 5  Introduction Synaptic Transmission Information transfer at a synapse Plays role in all the operations of the nervous system 1897: Charles Sherrington- “synapse” Chemical and electrical synapses 1921- Otto Loewi (frogs)...

SYNAPTIC TRANSMISSION Chapter 5  Introduction Synaptic Transmission Information transfer at a synapse Plays role in all the operations of the nervous system 1897: Charles Sherrington- “synapse” Chemical and electrical synapses 1921- Otto Loewi (frogs) 1959- Furshpan and Potter (crayfish)  Types of Synapses Electrical Synapses Allow direct transfer of ionic current from one cell to next Gap junction Channel made of 2 Connexons Connexons formed by 6 connexins 20 different connexins known Cells are said to be “electrically coupled” Flow of ions from cytoplasm to cytoplasm Pore about 1-2nm (large) Allows ions and many small organic molecules to pass Movement can be bidirectional Very fast transmission Leads to postsynaptic potentials (PSPs) Small (1mV) Synaptic integration: Several PSPs occurring simultaneously to excite a neuron (i.e. causes AP) Brain Stem (breathing), Interneurons in cerebral cortex, thalamus, cerebellum, hypothalamus (vasopressin and oxytocin) Early development  TYPES OF SYNAPSES Chemical Synapses Synaptic Cleft (20-50nm) Filled with fibrous extracellular proteins Use: Synaptic vesicles Secretory granules (dense core vesicles) Membrane differentiations Active Zones (Pre-synaptic) Postsynaptic density (Post-synaptic) Types of Synapses CNS Synapses Axodendritic Axon to dendrite Axosomatic Axon to cell body Axoaxonic Axon to axon Dendrodendritic Dendrite to dendrite  Types of Synapses CNS Synapses Gray’s Type I Asymmetrical, excitatory Gray’s Type II Symmetrical, inhibitory Types of Synapses The Neuromuscular Junction Studies of NMJ established principles of synaptic transmission Synapses between axons of motor neurons of spinal cord and skeletal muscle Axons of the Autonomic Nervous System innervate glands, smooth muscle and heart. Synapse at neuromuscular junction called End Plate and change in membrane potential termed End Plate Potential If EPP strong enough, leads to muscle contraction Most of this determined in frogs by Bernard Katz (1952)  Basic Steps Neurotransmitter synthesis Principles of Load neurotransmitter into synaptic vesicles Chemical Vesicles fuse to presynaptic terminal Neurotransmitter spills into synaptic Synaptic cleft Binds to postsynaptic receptors Transmission Biochemical/Electrical response elicited in postsynaptic cell Removal of neurotransmitter from synaptic cleft  Neurotransmitters Amino acids: Small organic molecules Principles of Glutamate, Glycine, GABA Chemical Amines: Small organic molecules Dopamine, Acetylcholine, Histamine Synaptic Peptides: Short amino acid chains (i.e. proteins) stored in and released from Transmission secretory granules Somatostatin, Thyrotropin Releasing Hormone, Neuropeptide Y Neurotransmitters  Principles of Chemical Synaptic Transmission Neurotransmitter Release Exocytosis: Process by which vesicles release their contents Mechanisms Action potential arrives at terminal Process of exocytosis stimulated by increase of intracellular calcium, [Ca2+]i, via voltage gated calcium channel Proteins alter conformation – activated (SNAREs) Vesicle membrane incorporated into presynaptic membrane Neurotransmitter released Vesicle membrane recovered by endocytosis Calcium Channels Channel composed of a single gene product Like Na+ channel Selectivity filter = tight ring of amino acids (different from Na+) Several different types N-and P-type Synaptic transmission in most neurons (presynaptic) T-type (“transient”) Activated by small depolarizations Influence likelihood of spiking L-type Muscle contraction Synaptic transmission in some sensory cells IP3 receptor Important in intracellular signaling Releases Ca2+ from endoplasmic reticulum Principles of Chemical Synaptic Transmission Neurotransmitter receptors: Ionotropic Transmitter-gated ion channels Four or five subunits join and form pore Closed in absence of ligand Ligand (neurotransmitter) binds leading to conformational change Less selective for ions versus voltage gated channels “Faster” pathway  Metabotropic: G-protein-coupled receptor  Slower and longer lasting signal Three steps: Metabotropic: Neurotransmitter binds to receptor Receptor activate G protein G-protein- G protein activates effector protein coupled Ion channel Enzyme that make secondary receptor messenger Can regulate ion channels, cellular metabolism, or gene expression  Principles of Chemical Synaptic Transmission Excitatory and Inhibitory Postsynaptic Potentials EPSP Transient postsynaptic membrane depolarization by presynaptic release of neurotransmitter IPSP Transient hyperpolarization of postsynaptic membrane potential caused by presynaptic release of neurotransmitter  Principles of Chemical Synaptic Transmission Neurotransmitter Recovery and Degradation Diffusion: Away from the synapse Reuptake: Neurotransmitter re- enters presynaptic axon terminal Mediated by clathrin protein Enzymatic destruction inside terminal cytosol or synaptic cleft Desensitization: e.g., AChE cleaves Ach to inactive state  Neuropharmacology Effect of drugs on nervous system tissue Receptor antagonists: Inhibitors of Principles of neurotransmitter receptors Curare (arrow tip poison used in Chemical South American natives to paralyze their prey; blocks muscle contraction at ACh Synaptic receptors) Receptor agonists: Mimic actions of Transmission naturally occurring neurotransmitters Nicotine (binds ACh receptor and activates skeletal muscle and CNS, but not heart) Defective neurotransmission: Root cause of neurological and psychiatric disorders Principles of Synaptic Integration Synaptic Integration Process by which multiple synaptic potentials combine within one postsynaptic neuron Quantal Analysis of EPSPs Katz (1952) Discovered spontaneous changes in muscle cell membrane potential occur in absence of stimulation Changes had same shape as EPPs, but much smaller (~1mV) compared to EPP (50mV) Coined the term MEPPs (miniature end plate potentials, or minis) Synaptic vesicles: Elementary units of synaptic transmission Quantum: An indivisible unit (reflects number of transmitter molecules in single vesicle and number of postsynaptic receptors available at synapse). Quantal analysis: Used to determine number of vesicles that release during neurotransmission Neuromuscular junction: About 200 synaptic vesicles, EPSP of 40mV or more CNS synapse: Single vesicle, EPSP of few tenths of a millivolt Principles of Synaptic Integration EPSP Summation Allows for neurons to perform sophisticated computations Integration: EPSPs added together to produce significant postsynaptic depolarization Spatial: EPSP generated simultaneously in different spaces Temporal: EPSP generated at same synapse in rapid succession (within 1-15msec of one another)  Principles of Synaptic Integration Contribution of Dendritic Properties to Synaptic Integration Dendrite as a straight cable Membrane depolarization falls off exponentially with increasing distance Vx = Vo/ex/  Vx depolarization of membrane at given distance Vo depolarization at origin, e is base of natural logarithms, x is distance to synapse and Dendritic length constant (; index of how far depolarization can spread down dendrite or axon) When x = , simplifies to Vx = Vo/e or V  = 0.37(Vo) The distance , where the depolarization is about 37% of that at the origin, is called the dendritic length constant The longer the length constant, the more likely EPSPs generated at distant synapses will depolarize the membrane at hillock  depends on 1) internal resistance (ri) and 2) membrane resistance (rm)  will decrease as internal resistance increases  will increase as membrane resistance increases Synaptic current will flow farther down a wide dendrite (low ri) with fewer open membrane channels (high rm)  Principles of Synaptic Integration Excitation Dendrites CAN have some (very few) voltage-gated sodium, calcium, and potassium channels Can act as amplifiers, but not enough to generate an action potential like axons Inhibition Action of synapses to take membrane potential away from action potential threshold Most permeable only to Cl-, allowing Cl- to flow inward toward equilibrium potential (-65mV) Exerts powerful control over neuron output IPSPs and Shunting Inhibition Excitatory vs. inhibitory synapses: Bind different neurotransmitters, allow different ions to pass through channels Membrane potential less negative than -65mV = hyperpolarizing IPSP Shunting Inhibition: Inhibiting current flow from soma to axon hillock  Principles of Synaptic Integration Modulation Synapses with G protein coupled receptor not directly associated with ion channel Synaptic transmission that modifies effectiveness of EPSPs generated by other synapses with transmitter-gated ion channels Example: Activating NE β receptor Closing of potassium channel reducing K+ conductance while increasing dendritic membrane resistance Leads to an increase in length constant Weak excitatory synapses will become more effective in depolarizing spike initiation zone beyond threshold (more excitable)!