05-SynapticTransmission-Fall2024.pdf

Synaptic Transmission Chapter 5  – Discuss the function & anatomy of synapses – Learn about the 2 types of synapses: electrical and chemical Learning – Understand all of the steps of neurotransmitter release at the chemical synapse objecti...

Synaptic Transmission Chapter 5  – Discuss the function & anatomy of synapses – Learn about the 2 types of synapses: electrical and chemical Learning – Understand all of the steps of neurotransmitter release at the chemical synapse objectives – Learn about the different categories of neurotransmitters – Discuss how post-synaptic potentials are summated with synaptic integration  – Synaptic transmission – Information transfer between neurons occurs at a synapse – Think of service network that sends texts between devices; even if you compose a text, if there is no service the message will not be transmitted Synaptic – The cornerstone of all the operations of the nervous system transmission – 1897: Charles Sherrington coins name overview “synapse” – Chemical and electrical synapses – 1921—Otto Loewi shows synaptic transmission is chemically mediated – Bathing frog hearts in acetylcholine juice – Late 1950s—Furshpan and Potter show existence of electrical synapses – First understood in lobsters  – Direction of information flow – Generally in one direction: neuron to target cell – First neuron: presynaptic neuron – Target cell: postsynaptic neuron Directionality of synapses  – Possible anatomical synapse connections include: – Axodendritic: axon to dendrite – Axosomatic: axon to cell body – Axoaxonic: axon to axon – Axospinous: axon to dendritic spine – Dendrodendritic: dendrite to dendrite Directionality of synapses  – Electrical synapses are extremely fast and often bidirectional – Gap junctions connect neuronal cell membranes directly – Channels form open pores between adjacent cells – Connexon—formed by six connexins – Cells said to be “electrically coupled” – Flow of ions from cytoplasm of one cell to cytoplasm of another cell – Cells excite one another via postsynaptic potentials (PSPs) Electrical synapses  – Electrical synapses are extremely fast and often bidirectional – Gap junctions connect neuronal cell membranes directly – Channels form open pores between adjacent cells – Connexon—formed by six connexins – Cells said to be “electrically coupled” – Flow of ions from cytoplasm of one cell to cytoplasm of another cell – Cells excite one another via postsynaptic potentials (PSPs) Electrical synapses  – Chemical synapses are the most common type of synapse in the nervous system (& arguably the most important) – Pre and post-synaptic neuron are anatomically separated by space called the synaptic cleft – Requires release of neurotransmitter chemicals from pre to post- synaptic neuron – Chemical message is converted into electrical message at the postsynaptic neuronal membrane Chemical synapses  – Chemical synapses are the most common type of synapse in the nervous system (& arguably the most important) – Pre and post-synaptic neuron are anatomically separated by space called the synaptic cleft – Requires release of neurotransmitter chemicals from pre to post- synaptic neuron – Chemical message is converted into electrical message at the postsynaptic neuronal membrane Chemical synapses  – Chemical synapses are the most common type of synapse in the nervous system (& arguably the most important) – Pre and post-synaptic neuron are anatomically separated by space called the synaptic cleft – Requires release of neurotransmitter chemicals from pre to post- synaptic neuron – Chemical message is converted into electrical message at the postsynaptic neuronal membrane Chemical synapses  – Studies on the neuromuscular junction (NMJ) pioneered our Chemical understanding of the principles underlying chemical synaptic synapses transmission – Fun fact – first studied in crawfish from the 1930’s – 1960’s!  1. Neurotransmitter synthesis 2. Load neurotransmitter into synaptic vesicles Steps of 3. Vesicles fuse to presynaptic terminal due to Ca2+ chemical 4. Neurotransmitter spills into synaptic cleft synaptic 5. Binds to postsynaptic receptors transmission 6. Biochemical/electrical response elicited in postsynaptic cell 7. Removal of neurotransmitter from synaptic cleft  1. Neurotransmitter synthesis 2. Load neurotransmitter into synaptic vesicles 3. Vesicles fuse to presynaptic terminal due to Ca2+ 4. Neurotransmitter spills into synaptic cleft 5. Binds to postsynaptic receptors 6. Biochemical/electrical response elicited in postsynaptic cell Steps of 7. Removal of neurotransmitter from synaptic cleft chemical synaptic transmission  1. Neurotransmitter synthesis 2. Load neurotransmitter into synaptic vesicles 3. Vesicles fuse to presynaptic terminal due to Ca2+ 4. Neurotransmitter spills into synaptic cleft 5. Binds to postsynaptic receptors 6. Biochemical/electrical response elicited in postsynaptic cell Steps of 7. Removal of neurotransmitter from synaptic cleft chemical synaptic transmission  – Process of exocytosis stimulated by intracellular calcium [Ca2+]i – Proteins alter conformation—activated – Vesicle membrane incorporated into presynaptic membrane – Neurotransmitter released into cleft – Vesicle membrane recovered by endocytosis Neurotransmitter release is mediated by calcium  – All our neurotransmitters fall into 1 of 3 categories: – Amino acids: small organic molecules— vesicles – Examples: glutamate, glycine, GABA – Amines: small organic molecules—vesicles – Examples: dopamine, acetylcholine, histamine Categories of neurotransmitters – Peptides: short amino acid chains (proteins)— secretory granules – Examples: dynorphin, enkephalins  – Neurotransmitters each have specific receptors on the postsynaptic neuronal membrane at the synaptic cleft – Either ligand-gated ion channel or G protein-coupled receptor – Therefore each neurotransmitter has an overall different effect on the postsynaptic cell Effects of neurotransmitters  – Neurotransmitters each have specific receptors on the postsynaptic neuronal membrane at the synaptic cleft – Either ligand-gated ion channel or G protein-coupled receptor – Therefore each neurotransmitter has an overall different effect on the postsynaptic cell Effects of neurotransmitters  – Neurotransmitter receptors that are ligand-gated ion channels function to elicit an excitatory or inhibitory effect on the postsynaptic cell: – EPSP (excitatory post-synaptic potential): transient postsynaptic membrane depolarization caused by presynaptic release of neurotransmitter Effects of neurotransmitters  – Neurotransmitter receptors that are ligand-gated ion channels function to elicit an excitatory or inhibitory effect on the postsynaptic cell: – IPSP (inhibitory post-synaptic potential): transient hyperpolarization of postsynaptic membrane potential caused by presynaptic release of neurotransmitter Effects of neurotransmitters  – Neurotransmitter receptors that are G protein-coupled receptors involve more steps and can enact more complex, long-term changes in the post-synaptic neuron – Basis of neuroplasticity / learning & memory! Effects of neurotransmitters  – Neurotransmitter receptors that are G protein-coupled receptors involve more steps and can enact more complex, long-term changes in the post-synaptic neuron – Basis of neuroplasticity / learning & memory! Effects of neurotransmitters  – Autoreceptors are receptors commonly found in membrane of presynaptic axon terminal – Presynaptic receptors sensitive to the neurotransmitter released by the presynaptic terminal called autoreceptors – Consequences of activating autoreceptors vary—common effect is inhibition of neurotransmitter release. – Appear to function as a sort of safety valve Autoreceptors  – Diffusion of transmitter molecules away from the synapse – Reuptake: Neurotransmitter reenters presynaptic axon terminal. – Enzymatic destruction inside Neurotransmitter terminal cytosol or synaptic cleft reuptake/ – Desensitization: for example, clearance & AChE cleaves Ach to render it inactive. degradation – Timing of neurotransmitter reuptake is manipulated pharmacologically to treat medical conditions! – SSRIs = selective serotonin reuptake inhibitors  – Neuropharmacology is the study of effects of drugs on nervous system tissue – Receptor antagonists: inhibitors of (turn off) neurotransmitter receptors – Example: curare – Receptor agonists: mimic actions (turn on) of naturally occurring neurotransmitters – Example: nicotine – Defective neurotransmission is the root cause of most Neuropharmacology neurological and psychiatric disorders.  – Synaptic integration is the process by which multiple synaptic potentials combine within one postsynaptic neuron – Neurons consider the cumulative effect more heavily than any individual effect over a set period of time Synaptic – Most CNS neurons receive thousands integration of synaptic inputs at a time – How do you choose what to do?! Answer: ”weighted voting” aka consider the accumulation of all the recent inputs – Basis of all neural computation  – The mathematical basis of synaptic integration lies in the amount of neurotransmitter vesicles released – Because you can generally assume a linear relationship (to an extent!) between amount of neurotransmitter and amount of excitation/inhibition Synaptic – Synaptic vesicles: elementary units of integration synaptic transmission – Quantum: an indivisible unit (usually 1 vesicle; you won’t have partial vesicle release) – Release of 1 vesicle aka 1 quantum causes 1 minature postsynaptic potential (“mini”)  – Quantal analysis: used to determine number of vesicles that release during neurotransmission – Example: at neuromuscular junction, about 200 synaptic vesicles— EPSP of 40 mV or more – At many CNS synapses, a single vesicle—miniature EPSP of few tenths of a millivolt Synaptic – But, enough miniEPSPs add up to full EPSPs! integration  – EPSP summation – Allows for neurons to perform sophisticated computations – Integration: EPSPs added together to produce significant postsynaptic depolarization – Spatial summation: EPSPs generated simultaneously at different sites – Temporal summation: EPSPs generated at same synapse in rapid succession Synaptic integration  – Dendrites are most often responsible for communicating synaptic integration; their contribution can be thought of as a hose (that passes current instead of water) – Simplified view Synaptic – Dendrite can be viewed as a straight cable. integration – Membrane depolarization falls off exponentially with increasing distance along the cable. – Vx = Vo/ex/ l – Dendritic length constant (l) – In reality, dendrites are very elaborate structures that contribute to more complex integrative properties.  – Dendrites are not always just passively transmitting current – Many dendrites have voltage- gated sodium, calcium, and potassium channels. Synaptic – Can act as amplifiers of integration postsynaptic potentials (vs. passive) – Dendritic sodium channels in some cells may carry electrical signals in opposite direction—from soma outward along dendrites.  – Not all synapses are excitatory; inhibitory synapses are equally as important – Action of inhibitory synapses—Take membrane potential away from action potential threshold. – Inhibitory synapses exert powerful control over neuron output. Inhibitory synapses  – Not all synapses are excitatory; inhibitory synapses are equally as important – Action of inhibitory synapses—Take membrane potential away from action potential threshold. – Inhibitory synapses exert powerful control over neuron output. Inhibitory synapses  – Excitatory vs. inhibitory synapses: bind different neurotransmitters, allow different ions to pass through channels Inhibitory – Membrane potential less negative than −65 mV = hyperpolarizing synapses IPSP – Shunting inhibition: Synapse inhibits current flow from soma to axon hillock.  – Excitatory synapses—glutamate – Gray’s type I morphology – Inhibitory synapses —GABA or glycine – Gray’s type II morphology – In addition to on dendrites, clustered on soma and near axon Excitatory vs. hillock inhibitory synapses  – Chemical synaptic transmission is at the heart of all neuroscience. Why do we – Rich diversity allows for complex behaviors. care so much – Provides explanations for drug effects about – Defective transmission is the basis for many neurological and psychiatric disorders. synapses? – Key to understanding the neural basis of learning and memory Quiz hint! – Steps of chemical synaptic transmission Questions?