The Synaptic Transmission PDF

# The Synaptic Transmission ## Sir John Carew Eccles, Alan Lloyd Hodgkin and Andrew Fielding Huxley - Awarded the Nobel Prize in Physiology or Medicine in 1963 - For their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of t...

# The Synaptic Transmission ## Sir John Carew Eccles, Alan Lloyd Hodgkin and Andrew Fielding Huxley - Awarded the Nobel Prize in Physiology or Medicine in 1963 - For their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the cell membrane of neurons ## Synapse - A specialized area of contact between neurons where they communicate with each other or with another cell (muscle or gland). - The cell that sends the signal is defined as presynaptic and the one that receives the signal is called postsynaptic. - The space that physically separates the two communicating cells is the intersynaptic space or synaptic cleft. ## Differences between electrical and chemical synapses ### Electrical Synapse - Terminal axon of the presynaptic cell - Plasmatic membrane of the terminal axon - Gap junctions - Plasmatic membrane of the postsynaptic cell ### Chemical Synapse - Terminal axon of the presynaptic cell - Vesicles that release neurotransmitter - Neurotransmitter-binding receptors - Intersynaptic space or synaptic cleft - Plasmatic membrane of the postsynaptic cell ### Information about the differences between electrical and chemical Synapse - In an electrical synapse, the plasmatic membranes of the presynaptic cell and the postsynaptic cell are in direct contact. - The flow of ions through the gap junctions that connect the two membranes allows the impulses to pass directly to the postsynaptic cell. - In a chemical synapse, the plasmatic membranes of the presynaptic cell and the postsynaptic cell are separated by a narrow synaptic cleft. - The neurotransmitter molecules diffuse through the cleft and bind to receptors located on the postsynaptic membrane. - Binding leads to the opening of channels that promote the flow of ions which can give rise to a new impulse in the postsynaptic cell. ### Neurotransmitters - Substances synthesized in the pre-synaptic neuron that transmit information between neurons. ## The Structure of Electrical and Chemical Synapse **Electrical Synapse** * 2-4 nm * Gap junction: cytoplasm of the two cells is directly connected **Chemical Synapse** * 20-50 nm * Intersynaptic space: the two cells are completely separated, not connected. ## Electrical Synapses - Rare in the nervous system - The wave of depolarization of the action potential passes from one cell to another through a specialized structure called a gap junction or tight junction. - The pre and post synaptic membranes are very close (electrically coupled). There is the presence of specialized structures: connexons (formed by 6 connexins) that constitute real bridges. - Cytoplasmic, it is much wider than ionic channels and allows all types of ions and also small organic molecules (nucleotides, sugars, amino acids...). - It is not an exclusive structure of neurons: it is found in many tissues and serves to coordinate the activities of cells that work synchronously (liver tissue, epithelial, smooth muscle fibers and cardiac...). - Signals such as a drop in pH or an increase in intracellular Ca2+ concentration in one of the two cells induce the closure of the channel. - Extremely fast and bidirectional (in invertebrates, they are common in neurons that regulate escape reflexes). However, some synapses can show the phenomenon of rectification, that is, the preference for conduction of the stimulus in one direction rather than another. ## Chemical Synapses - Made up of three elements * Presynaptic element: terminal axon. * Synaptic space * Postsynaptic element: dendrite, soma, axon with receptors that receive the signal. - The pre-synaptic and post-synaptic membranes of a chemical synapse are separated by the intersynaptic space or synaptic cleft (20-50 nm) 10 times wider than the space that separates the gap junctions. * Terminal axon contains small spheres (about 50nm) called synaptic vesicles that contain the neurotransmitter. * Other vesicles of larger dimensions (about 100 nm), called secretory granules contain soluble proteins. * The accumulations of proteins adjacent to the membranes and inside the membranes are called membrane specializations. * The pre-synaptic neuron releases the chemical messenger (neurotransmitter) that crosses the synaptic cleft and acts on specialized proteins of the post-synaptic membrane (post-synaptic density) modifying its permeability to ions. This modification determines a change in the potential of the post-synaptic neuron called the post-synaptic potential. * These synapses are less rapid, unidirectional but more modifiable than electrical synapses. They transform electrical signals into chemical signals. * Synapses in which specializations of the membrane on the postsynaptic side are denser than on the presynaptic side are called asymmetric or type I Gray synapses and tend to be excitatory synapses. * Synapses in which specializations of membrane have a similar thickness are called symmetric or type II Gray synapses and are generally inhibitory. ## Nobel Prize in Physiology or Medicine 1936 - Otto Loewi demonstrated the chemical nature of nerve transmission. He used two frog hearts. - He inserted the two hearts in two containers in physiological solution, then he electrically stimulated one heart to induce a slowing of the heart rate. - He took the saline solution from the first heart that contained the substances released from the electrically stimulated heart and inserted it into the second container: The second heart, which had been proceeding at a normal rate, slowed down. * This demonstrated that in the first heart there was a substance that was transferred to the second container and that transmitted the message of the electrical impulse: The substance in question is Acetylcholine, one of the most important neurotransmitters. ## Neuromuscular junction - The synapse between the motor neurons of the spinal cord and the muscle fibers of skeletal muscles. - The axon of the motor neurons near the muscle fiber branches to give rise to a series of presynaptic terminals with numerous active zones. - The motor endplate (postsynaptic membrane) contains folds rich in receptors. - It releases a much greater amount of neurotransmitters than other synapses, and, in fact, every motor neuron action potential is followed by an action potential in the fiber, with consequent contraction. ## In Synthesis ### Electrical Synapse * Action potential passes directly from the presynaptic cell to the postsynaptic cell. ### Chemical Synapse * The action potential generated by the presynaptic cells causes the exocytosis of synaptic vesicles and the release of a chemical messenger (neurotransmitter) that binds to a receptor on the postsynaptic membrane. * This generates an electrical signal. ## Neurotransmitters **Neurotransmitters** - Convert electrical nerve stimuli, represented by action potentials, into chemical nerve stimuli, consisting of neurotransmitter molecules that can have a protein or lipid nature. - Neurotransmitters can be distinguished into two major categories: * **Low molecular weight neurotransmitters (amino acids and amines)**: generally mediate rapid reactions. * **High molecular weight neurotransmitters (neuropeptides)**: tend to modulate slower and continuous functions. **General Characteristics of Neurotransmitters** - Synthesized differently and have different release conditions. - Bind to receptors on the postsynaptic membrane and tend to alter the electrical properties of the postsynaptic cell. **Main neurotransmitters** * **Low molecular weight** * **Amino acids** * Gamma-aminobutyric acid (GABA) * Glutamate (Glu) * Glycine (Gly) * **Amines** * Acetylcholine (ACh) * Dopamine (DA) * Adrenaline * Histamine * Noradrenaline (NA) * Serotonin (5-HT) * **High molecular weight** * **Peptides** * Cholecystokinin (CCK) * Dynorphin * Encephalins (Enk) * N-acetylaspartylglutamate (NAAG) * Neuropeptide Y * Somatostatin * Substance P * Thyrotropin-releasing hormone * Vasoactive intestinal polypeptide (VIP) **The cycle of activity of all neurotransmitters is similar and includes the following steps:** * Stored in presynaptic vesicles (50nm) or secretory granules (100nm). * Released into the synaptic cleft following exocytosis of vesicles or secretory granules. * Interact with specific receptors on the postsynaptic membrane. * Rapidly removed (through re-uptake in the pre or postsynaptic membrane and of astrocytes) or degraded by enzymes such as peptidase in the synaptic space to prevent them from continuing to transmit the signal. **Low Molecular Weight Neurotransmitters** * **The synthesis of low molecular weight neurotransmitters in the axon terminal** * Synthesized in the cytosol of the axon terminal and, subsequently, transported by active transport. They are absorbed into the vesicles present in the axon terminal. * The enzymes necessary for their synthesis are synthesized in the soma and transported along the axon through axonal flow. The precursors necessary (amino acids) for the synthesis of neurotransmitters (e.g. tyrosine for dopamine, adrenaline and noradrenaline) are derived from a re-uptake (re-uptake) at the level of the presynaptic membrane. **Vesicles** * Initially produced by the cell body at the Golgi apparatus level, they are then transported by axonal flow to the presynaptic terminal where they become available to be filled with neurotransmitters. * The neurotransmitter is incorporated into the synaptic vesicles by a vesicle transporter present on the vesicle membrane that mediates active transport, secondary to the antiport type. * These proteins cause the neurotransmitter to enter, exploiting the electrochemical gradient of H+ ions generated and maintained by a proton pump (V-ATPase), present on the vesicle membrane. * The pump accumulates H+ inside the vesicle with ATP expenditure, then releases H+ and leads to the entry of neurotransmitters. * There are two types of vesicles in the presnaptic terminal. * **Reserve Deposit** --- These vesicles are located away from the presynaptic membrane, bound to the cytoskeleton. As vesicles from the release pool are exocytosed, the vesicles from the reserve pool can be released from the cytoskeleton and directed towards the active zones, to replace the vesicles of the release pool. * **Release Deposit** --- These vesicles are located near the presynaptic membrane, in correspondence to the active zones and are available for exocytosis. * The passage of the vesicles from the reservoir pool to the release pool is regulated by the increase of Ca2+ in the presynaptic terminal, which also causes exocytosis of the vesicles. **High Molecular Weight Neurotransmitters** * Fragments of longer polypeptide chains, synthesized in the rough endoplasmic reticulum. * The chain is cleaved by the action of enzymes (proteases) that generate smaller fragments, some of which constitute the neuropeptide as such or its precursor, which are packaged into secretory granules, which bud from the Golgi apparatus: the axonal flow transports the granules to the axon terminal where they release the neurotransmitter into the synaptic cleft for exocytosis. **Release of neurotransmitters** - Each cell only releases one type of low molecular weight neurotransmitter (eg. glutamate or only GABA which is an inhibitory neurotransmitter.) - However, within the same terminal, synaptic vesicles for a low molecular weight neurotransmitter may be present and secretory granules for a neuropeptide. **Mechanism of vesicle release** - The mechanisms of exocytosis involve the interaction of two proteins: `v-SNARE` and `t-SNARE``. These proteins allow the release of the neurotransmitter. * **V-SNARE** - A class protein associated with the vesicle membrane * **t-SNARE** --- A class of protein bound to the presynaptic plasma membrane at the level of the active zones * Both contain a hydrophobic domain that attaches to the respective membranes and a hydrophilic domain that is in contact with the cytosol. The interaction between the two proteins guides the vesicle close to voltage-gated Ca2+ channels. These channels are located in the section of the membrane that does not contain voltage-gated channels of Na+ or K+. These channels open when the internal environment depolarizes due to the arrival of the action potential: the extracellular concentration of ions is very low, so their passage into the cell does not have consequences on the membrane potential but has metabolic effects. * **Nucleation** The cytoplasmic sections of v-SNARE and t-SNARE proteins are complementary, they bind to each other with a reciprocal helical winding. * **Closure to a zipper** The helical winding leads to the development of a powerful force that brings the vesicle membrane into contact with the presynaptic membrane. ** The fusion of the vesicle with the presynaptic membrane** * It is promoted by the binding of 4 Ca2+ ions to synaptotagmin (a transmembrane protein located on the synaptic vesicle membrane) * The binding of Ca2+ to synaptotagmin induces a conformational change that allows it to bind to membrane phospholipids, leading to the formation of a fusion pore. **The release of each vesicle** * Contains a fixed amount or "quantum" of neurotransmitters, because the vesicles all have similar dimensions: The release of neurotransmitters is called "quantal release". * A higher concentration of Ca2+ ions determines the fusion of a larger number of vesicles and the release of more neurotransmitter in the synaptic cleft. * The concentration of Ca2+ in the cytoplasm depends on the frequency of action potentials in the presynaptic neuron. * The higher the frequency of action potentials arriving at the presynaptic terminal, the higher the concentration of Ca2+ in the terminal and, consequently, the greater the amount of neurotransmitter released. ### Endocytosis - It follows the exocytosis of vesicles. It removes the vesicle membrane to maintain a constant extension, thanks to endocytosis mediated by the intervention of the proteins: * **Clathrin** --- It induces the curvature of the membrane and the formation of a coated vesicle structure. * **Dynamin** --- It wraps, shrinks and detaches the vesicle from the membrane by hydrolyzing GTP molecules. * The newly formed vesicle can then be directed towards the reserve pool where it is refilled with neurotransmitters by vesicle transporters. ### Synthesizing the Chemical Synapse * The neurotransmitter is stored * The action potential arrives at the presynaptic terminal, spreading along the axon. * Voltage-gated calcium channels open, allowing calcium to enter the neuron * Calcium ions present in the synaptic cleft cause vesicle exocytosis. * The neurotransmitter is released and diffuses into the synaptic cleft. * It binds to specific receptors on the postsynaptic membrane, opening them. * This triggers an excitatory postsynaptic potential in the postsynaptic neuron. * Removal of neurotransmitters to ensure that the postsynaptic neuron can respond to subsequent signals. ### Postsynaptic potential - When neurotransmitters bind to their specific receptor, variations occur in the membrane potential (postsynaptic potential). - They are graded and proportional to the amount of neurotransmitters released from the presynaptic membrane. **Postsynaptic potential types** * **Excitatory Postsynaptic Potential (EPSP)**: The membrane potential moves closer to the threshold; sodium ions, carrying a positive charge, are moving into the cell. * **Inhibitory Postsynaptic Potential (IPSP)**: The membrane potential moves further away from the threshold; chloride ions, carrying a negative charge, are moving into the cell or potassium ions, carrying a positive charge, are moving out of the cell ### **Postsynaptic Delay** - The time between the appearance of an action potential at the axon terminal and the generation of the postsynaptic potential. - It is usually 0.5 milliseconds. - It is due to the diffusion of the neurotransmitter across the synaptic cleft. ### **Postsynaptic Potentials** - They are temporary changes in the membrane potential, evoked by chemical signals (neurotransmitters). - Their amplitude is smaller than that of action potentials (about 10 mV max) and their duration is longer (tens of milliseconds). - They are local potentials: The current that enters spreads through the dendrite and soma up to the axon hillock. - They are graded potentials: They are proportional to the amount of neurotransmitters released and they are summable. ### **Excitatory Synapses** - **The generation of an EPSP** - Neurotransmitters open cationic channels (Na+ and K+). - Sodium ions are flowing down their electrochemical gradient into the neuron. - **The outcome** is the depolarization of the postsynaptic membrane and an increase in the likelihood of generating an action potential in the postsynaptic neuron. ### **Inhibitory Synapses** - **The generation of an IPSP** - Neurotransmitters open Cl- channels (inward) or K+ channels (outward) - **The outcome** is the hyperpolarization of the postsynaptic membrane and a decrease in the likelihood of generating an action potential in the postsynaptic neuron. ### **Characteristics of the 2 main neurotransmitters** 1. **Glutamate** * Found mainly in excitatory synapses 2. **Gamma–aminobutyric acid (GABA)** * Found mainly in inhibitory synapses ### **How neurotransmitters operate** - Some neurotransmitters perform exclusively excitatory functions, such as glutamate. Some act as inhibitory neurotransmitters, such as GABA or GLY. Other neurotransmitters can have either an excitatory effect or an inhibitory effect, depending on the type of receptor or ion channel present in the postsynaptic membrane. * **Acetylcholine** * This neurotransmitter mediates the action of both excitatory and inhibitory synapses. * **Excitatory Effect** Mediates the contraction of skeletal muscles, by binding to ionotropic receptors. * **Inhibitory Effect** Mediates the slowing of the contraction of cardiac muscle, by binding to metabotropic receptors. ### **The Constant of Space** - The efficiency of an excitatory synapse to produce an action potential depends on the: * Distance of the synapse relative to the axon hillock. * Properties of the dendrite * ** The dissipation of the current** (the decay of the EPSP) * As the current travels away from the synapse, the amplitude of the EPSP decreases. * The constant of space shows how far the depolarization can spread along a dendrite or axon before it dissipates, due to the passing of the threshold. * The constant of space is the distance at which the potential drops 37% of its original value. * ** Factors that influence the constant of space** * **Rm**, The membrane resistance * This is the resistance to the flow of the current across the membrane * This is determined by the number of open ion channels. * **Ri** The internal resistance * This is the resistance to the flow of the current longitudinally within the dendrite. * This is determined by the diameter of the dendrite and the electrical properties of the cytoplasm. * **A neuron with a thicker diameter** (low Ri) or with fewer open ion channels (high Rm) will have a larger constant of space, allowing the depolarization to travel farther down the dendrite before decreasing. ### **Neural Integration** - Every neuron is synaptically connected with a multitude of other neurons. - Each neuron can receive thousands of synaptic inputs, but provides only one output, which is the result of the integration of excitatory and inhibitory signals. - The sum of the electrotonic currents arising from all postsynaptic potentials influences the membrane potential at the level of the axon hillock, determining whether or not the threshold is reached which determines the generation of the action potential and its frequency. ### **Methods of Neural Integration** * **Spatial summation** ---- This type of summation combines the effects of multiple synaptic inputs at different locations on the neuron, to generate a larger, more sustained postsynaptic potential. * **Temporal Summmation** ---- This type of summation combines the effects of multiple synaptic inputs that arrive at the same location on the neuron in rapid succession. * If the inputs arrive close enough in time, the postsynaptic potentials can add up to reach threshold, and trigger an action potential. **In general, the integration of excitatory and inhibitory inputs determines the firing frequency of the neuron. ** ## Examples of Synaptic Transmission * **Excitatory Synapses** * **Glutamate** * Opens cationic channels, causing membrane depolarization and leading to transmission of a nerve impulse to the postsynaptic neuron. * **Inhibitory Synapses** * **GABA and glycine** * Open chloride channels, leading to hyperpolarization, making it more difficult for a nerve impulse to be transmitted to postsynaptic neurons. ### **The Synaptic Integration** - The final output of a neuron is determined by the balance of excitatory and inhibitory inputs. - If excitatory inputs are stronger, the neuron is more likely to fire . - If inhibitory inputs are stronger, the neuron is less likely to fire an action potential. ### **Inhibitory Effects of Synapses** * ** Inhibitory synapses can reduce the excitability of neurons** * They can modulate the excitability of the postsynaptic neuron by inhibiting the release of neurotransmitters by the presynaptic neuron. * They can reduce the responsiveness of the postsynaptic neuron by decreasing its sensitivity to excitatory neurotransmitters. * **The Role of Inhibition in Neural Networks** * Inhibitory synapses play a pivotal role in shaping neural networks: * Inhibitory synapses allow for the control of the firing of neurons, preventing excessive firing. * They allow for the transmission of specific signals, by inhibiting the firing of neurons that are not relevant to the current task. * They help to synchronize the firing of neurons, allowing for coordinated activity. ### References: - Biologia Applicata * Pages 68-79