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SYNAPTIC TRANSMISSION 2012 Yasemin Keskin-Ergen Synapse • The point where the two neurons communicate. • The word comes from "synaptein", which Charles Scott Sherrington and colleagues coined from the Greek "syn-" ("together") and "haptein" ("to clasp"). Spinal motor neuron - 10.000 contacts - 2000 on its cell body - 8000 on its dendrites Purkinje cells ~150.000 contacts 2 Kandel et al. Principles of Neural Science, McGraw Hill, 2000 Synaptic transmission Electrical synapses Chemical synapses Electrical synapses are formed by gap junctions that allow direct passage of molecules between neurons, creating a cytoplasm-tocytoplasm connection They are more common in the central nervous system than previously thought. Gap junctions are found between glial cells as well. 3 Kandel et al. Principles of Neural Science, McGraw Hill, 2000 4 Kandel et al. Principles of Neural Science, McGraw Hill, 2000 Electrical Transmission Allows the Rapid and Synchronous Firing of Interconnected Cells Electrical transmission is useful for connecting large groups of neurons. Transmission across electrical synapses is extremely rapid because it results from the direct flow of current from the presynaptic neuron to the postsynaptic cell. Since current flows across the membranes of all electrically coupled cells at the same time, several cells can act coordinately as one large cell. Electrical synaptic transmission was first demonstrated at the giant motor synapse in the crayfish 5 Kandel et al. Principles of Neural Science, McGraw Hill, 2000 Electrical transmission is graded and occurs even when the currents in the presynaptic cell are below the threshold for an action potential. Gap-junction channels are relatively large and nonselective, they allow passage of large cation and anions, and compounds like chemical messengers (e.g., IP3, small peptides) to flow through. 6 Kandel et al. Principles of Neural Science, McGraw Hill, 2000 Distinguishing properties of electrical and chemical synapses Type of synapse Distance between cell membranes Agent of transmission Synapitc delay Direction of transmission Electrical 3.5nm Ion current Virtually absent Usually bidirectional Chemical 20-40nm Chemical transmitter At least 0.3ms usually 1-5ms Unidirectional 7 Kandel et al. Principles of Neural Science, McGraw Hill, 2000 CHEMICAL SYNAPSES Axosomatic synapse: between axon terminal of a neuron (sender) and cell body of a target cell (receiver) Axodendritic synapse: between axon terminal of a neuron (sender) and dendrite of target cell (receiver) InterActive Physiology 10-System Suite. (Cummings Publishing Company), 2006 8 Ligand gated ion channels: ACh: Acetylcholine Ligand-gated ion channel receptors: The channel opens with binding of a specific neurotransmitter ionic flow change in mebrane potential of postsynaptic membrane (postsynaptic potentials) These channels are mostly located on the dendrites and the cell body (receptive portion) 9 InterActive Physiology 10-System Suite. (Cummings Publishing Company), 2006 Neurotransmitters act either directly or indirectly on ion channels that regulate current flow in neurons Ionotropic receptor Metabotropic receptor 10 Kandel et al. Principles of Neural Science, McGraw Hill, 2000 1.AP reaches the presynaptic axon terminal and causes the voltage gated Ca2+ channels to open Ca2+ Neurotransmitter vesicles 2. Presence of Ca2+ causes synaptic vesicles to fuse with membrane. 3. Neurotransmitters stored in vesicles are released and they diffuse across the synaptic cleft and bind to their receptors over the postsynaptic membrane 4. These receptors change the membrane potential directly or indirectly by changing the membrane permeability to the specific ions 5. Based on the neurotransmitter and/or reecptor type Depolarization Hyperpolarization 11 InterActive Physiology 10-System Suite. (Cummings Publishing Company), 2006 Excitatory postsynaptic potential (EPSP) depolarize neurons 12 Kandel et al. Principles of Neural Science, McGraw Hill, 2000 The combination of excitatory and inhibitory synaptic connections mediating the stretch reflex of the quadriceps muscle is typical of circuits in the central nervous system. Neurotransmitter: glutamate Channels: glutamate-gated permeable to Na+. Neurotransmitter: Glycine Channels: ligand gated Clchannels 13 Kandel et al. Principles of Neural Science, McGraw Hill, 2000 14 Kandel et al. Principles of Neural Science, McGraw Hill, 2000 Synaptic potentials are graded potentials Neurotransmitter release is directly related with the Many EPSPs are needed to depolarize a neuron amount of Ca2+ that enters the presynaptic terminal. to the threshold. When the amount of Ca 2+ entering the presynaptic terminal is altered, the synaptic potential may be enhanced, or weakened. 15 InterActive Physiology 10-System Suite. (Cummings Publishing Company), 2006 Temporal & Spatial summation The EPSP produced by the one neuron often far below the threshold for generating an action potential. 16 INTEGRATION • Many EPSPs are needed to depolarize a neuron to the threshold. • IPSPs cancel the effects of excitatory activity and can prevent the postsynaptic cell form generating an action potential. • The closer a synapse is to the trigger zone, the greater the effectiveness of that synapse. 17 InterActive Physiology 10-System Suite. (Cummings Publishing Company), 2006 Signal Type Amplitude Duration (mV) Summation Effect of signal Type of propogation -Synaptic potentials 0.1-10 5ms-20min Graded Hyperpolarizing/ Passive Depolarizig - Action potential 70-100 1-10ms All-or-none Depolarizing Active 18 Kandel et al. Principles of Neural Science, McGraw Hill, 2000 Neurotransmitter effects The action of a transmitter in the postsynaptic cell does not only depend on the chemical properties of the transmitter but rather on the properties of the receptors that recognize and bind the transmitter. Major neurotransmitters: • Amino acids: glutamate, γ-aminobutyric acid (GABA), glycine • Monoamines and other biogenic amines: dopamine (DA), norepinephrine (noradrenaline; NE, NA), epinephrine (adrenaline), histamine, serotonin (SE, 5-HT) • Peptides: somatostatin, opioid peptides • Others: acetylcholine (ACh), adenosine, nitric oxide 19 Glutamate receptors • Ionotropic (named according to the types of synthetic agonists that activate them) – AMPA (a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid*) – Kainate – NMDA (N-methyl-D-aspartate) • Metabotropic 20 Kandel et al. Principles of Neural Science, McGraw Hill, 2000 Glutamate receptors Non-NMDA ionotropic receptors generate the large early component of the EPSP in most of the neurons. These receptors are permeable to both Na+ and K+ but are usually not permeable to Ca. The NMDA receptor-channel contributes to the late component of the EPSP. - NMDA receptor is permeable to Ca2+ as well as to Na+ and K +. - opening depends on membrane voltage as well as a chemical transmitter. When the membrane is depolarized Mg 2+ is expelled from the channel by electrostatic repulsion, allowing Na + and Ca2+ to enter. 21 Kandel et al. Principles of Neural Science, McGraw Hill, 2000 GABA Receptors • Gamma-aminobutyric acid (GABA) is a major inhibitory transmitter in the brain and spinal cord. • It acts on two receptors: GABAA and GABAB. • The GABAA receptor is an ionotropic receptor that gates a Cl - channel. • The GABAB receptor is a metabotropic receptor that activates a second-messenger cascade, which often activates a K + channel. GABAA Receptor 22 Termination of Synaptic Transmission Neurotransmitters dissociate from receptors Neurotransmitters must be reabsorbed or broken down once it reaches the synaptic cleft to prevent further excitatory or inhibitory signal transduction. Pumped into the presynaptic terminal Broken down by the enzymes Breakdown products are taken up by the presynaptic cell e.g., ACh is broken down by acetylcholinesterase (AChE). Choline is taken up and recycled by the pre-synaptic neuron to synthesize more ACh. Neurotransmitter resyntesized Neurotransmitters repacked into vesicles 23 Drug Action on Neurotransmission Many important psychopharmacological agents target: -Neurotransmitter receptors - Enzymes that regulate neurotransmitter synthesis or degradation - Neurotransmitter re-uptakers. Agonists of a neurotransmitter binds to its receptor and mimicks the endogenous neurotransmitter (e.g. A full agonist open the ion channel) Antagonist binds to receptor but stabilizes the channel in resting state (release of few ions). Resting state Full agonist opens the channels Antagonist stabilizes the channel in resting state Drug Action on Neurotransmission Positive allosteric modulation: potentiation of the channel by a substance other than the neurotransmitter.. (another binding site) NT1: Neurotransmitter PAM: Positive allosteric modulator Drug Action on Neurotransmission Negative allosteric modulation: The drug binds to the channel and blocks the channel reduce the effects of the neurotransmitter.. NT1: neurotransmitter NAM : negative allosteric modulator Drug Action on Neurotransmission Drugs can promote or inhibit the activity of presynaptic re-uptaker of the nerotransmitter (e.g. A re-uptake blocker would let a neurotransmitter to act on postsynaptic receptor for a longer period enhanced chemical signalling)