Neurophysiology and Information Christopher Fiorillo BiS 527, Spring 2010 042 350 4326, [email protected] Part 4: Synaptic Transmission Reading: Bear, Connors, and Paradiso Chapter 5 Or any other neuroscience textbook. A Single Neuron with Synapses in Yellow Synapses Are Physical Contacts between Neurons that Enable Fast Transmission of Information • Types of Synaptic Contacts – Axodendritic: Axon to dendrite – Axosomatic: Axon to cell body – Axoaxonic: Axon to axon – Dendrodendritic: Dendrite to dendrite Two Types of Synaptic Transmission • Chemical Transmission – 1921- Otto Loewi • Electrical Transmission – 1959- Furshpan and Potter • There was a long-lasting debate about whether transmission was chemical or electrical. Both occur, but chemical transmission is much more common. Direction of Information Flow • Information usually flows in one direction – First neuron = Presynaptic neuron – Target cell = Postsynaptic neuron Postsynaptic neuron Presynaptic neuron Electrical Synapses Are Composed of Gap Junctions • Gap junction are large channels – Large enough (1-2 nm) to allow all ions plus other small molecules to pass – A Connexon spans the membrane - formed by six connexin proteins • Cells are said to be “electrically coupled” – Flow of ions from cytoplasm to cytoplasm Electrical Synapses • Very fast transmission – Chemical transmission has a delay • Postsynaptic potentials (PSPs) have the same form as the presynaptic potential, but are smaller • Most electrical synapses are bidirectional, but some are unidirectional A Chemical Synapse • The synaptic cleft is a 20-50 nm gap between the presynaptic terminal and the postsynpatic membrane • Neurotransmitter is released into the cleft and activates postsynaptic receptors Electron Micrograph of a Chemical Synapse • Synaptic Vesicles – Made of phospholipid membrane – 50 nm in diameter – Filled with molecules of neurotransmitter • Dense-core Vesicles – Contains peptide neurotransmitters • Vesicles release neurotransmitter when they fuse with the presynaptic membrane Two Synaptic Morphologies • CNS Synapses (Examples) – Gray’s Type I: Asymmetrical, usually excitatory – Gray’s Type II: Symmetrical, usually inhibitory Synapses Vary in Size and Strength • Larger synapses allow the presynaptic neuron to have a larger and more reliable effect on the postsynaptic neuron • Neurotransmitter Synthesis and Storage – Small neurotransmitters (amines, amino acids) • Synthesized in vesicles within terminal – Peptides • Synthesized within soma and transported to terminal • Basic Steps of Chemical Synaptic Transmission – Action potential invades synaptic terminal – Depolarization-activated Ca2+ channels open – Ca2+ triggers vesicles to fuse into membrane of presynaptic terminal (exocytosis) – Neurotransmitter spills into synaptic cleft – Binds to postsynaptic receptors – Biochemical/Electrical response elicited in postsynaptic cell – Removal of neurotransmitter from synaptic cleft – New vesicles formed by endocytosis – Vesicles are filled with neurotransmitter and prepared for release Removal of Neurotransmitter from the Synaptic Cleft • Removal of neurotransmitter is important in order to limit the duration of postsynaptic stimulation. This enables high frequencies of information transmission • Three Mechanisms – Diffusion – Reuptake: Transporters bind neurotransmitter and transport it to inside of presynaptic terminal • This is the most important mechanism for removing neurotransmitters • Cocaine and Prozac (fluoxetine) block reuptake of dopamine and serotonin – Enzymatic destruction in synaptic cleft • Acetylcholineesterase eliminates acetylcholine. It is the only example of this method. Neurotransmitter Release is Quantal • A action potential causes the release of a discrete number of vesicles (or quanta) – Neuromuscular junction: About 200 synaptic vesicles, EPSP of 40mV or more – CNS synapse: Single vesicle, EPSP of few tenths of a millivolt • Each vesicle contains about the same amount of neurotransmitter – Quantal content (the amount of transmitter per vesicle) is not a physiologically important variable • Spontaneous release of a single vesicle causes a miniature postsynaptic potential (current) – Often called a “mini” The Neuromuscular Junction • Studies of NMJ established principles of synaptic transmission • Synapses between neurons are very similar to NMJ Miniature Postsynaptic Currents Are Caused by Release of a Single Vesicle • “Minis” (mEPSCs and mIPSCs) are caused by spontaneous release of a single vesicle in the absence of a presynaptic action potential • Minis can be calcium-dependent or independent • Time course of mPSCs are identical to PSCs Glutamate EPSC • ~3 ms for EPSC • ~30 ms for IPSC • Amplitude of mPSC depends on postysynaptic receptors • vesicles all contain the same amount of transmitter, which can saturate postsynaptic receptors • Frequency of mPSCs depends on presynaptic factors • At most synapses, < 0.01 mPSC / second • At some synapses, > 0.1 mPSC / second Release Probability • Not every action potential evokes vesicle release • Release probability (Pr) given action potential • Some synapses release multiple vesicles, but most release just 0 or 1 vesicle • Pr depends primarily on calcium concentration in terminal’s cytosol, which P varies from depends on: r – Presence or absence of an action potential one synapse to another. A – Recent history of action potentials typical value is – Activation of neurotransmitter receptors on 0.3. synaptic terminal Paired-Pulse Depression and Facilitation • PPD and PPF are universal features of synapses. • Some synapses show PPD, some show PPF, and some show both – All synapses may have multiple mechanisms mediating both depression and facilitation • PPD and PPF are caused primarily by a decrease or increase, respectively, in vesicle release probability • Electrical stimuli (each lasting about 0.2 ms) are applied to a brain slice maintained in vitro. This evokes postsynaptic potentials (or currents, if measured in voltage clamp). – Excitatory Postsynaptic Potential (Current): EPSP (EPSC) – Inhibitory Postsynaptic Potential (Current): IPSP (IPSC) • Each stimulus evokes action potentials in many axons, and it therefore causes vesicle release from many terminals – A PSP (PSC) is caused by release of multiple vesicles (quanta) • But if a low stimulation current is used, it is possible to stimulate only a single axon, and that axon may have only one release site. In this case, some stimuli may not release any vesicles. • The amplitude of a PSP (PSC) depends on the release probability at stimulated synapses Presynaptic [Ca2+] at PF synapse PPD and PPF at 3 synapses. 10 stimuli at 50 Hz (20 ms intervals) Causes of Synaptic Depression and Facilitation • The most common cause of facilitation is an increased calcium concentration – This is due primarily to the fact that calcium is cleared slowly after an action potential • The most common cause of depression is a loss of “docked” (releasable) vesicles – Most vesicles in the terminal are “undocked,” meaning that they are not close to the membrane and bound to the vesicle-release machinery – There may be just one docked vesicle. Once it is released, it takes time for another vesicle to be docked and ready to release. – The rate of recovery from depression (docing of vesicles) is increased by calcium • There are many ways in which release probability might be modified – Changes in membrane voltage – Changes in the properties of ion channels, particularly calcium channels, that are activated during the action potential – Modification of proteins involved in vesicle release • There are probably multiple depressing and facilitating processes happening simultaneously at each synapse. Presynaptic [Ca2+] at PF synapse PPD and PPF at 3 synapses. 10 stimuli at 50 Hz (20 ms intervals) Modulation of Release Probability by Presynaptic Neurotransmitter Receptors Presynaptic [Ca2+] at PF synapse Suppression of glutamate EPSCs by is suppressed by cannabinoid adenosine receptors receptor activation • Neurotransmitter receptors on presynaptic terminals act to augment or suppress release probability – These receptors therefore alter PPD or PPF • Many receptors suppress vesicle release, including “autoreceptors” – Suppression often occurs through inhibition of Ca2+ channels and activation of K+ channels How can we know whether a change in amplitude of a synaptic potential is pre- or postsynaptic? Suppression of glutamate EPSCs by adenosine receptors • Two Easy Tests: – Paired-pulse ratio (PPF or PPD) • A change suggests a presynaptic effect • No change suggests a postsynaptic effect – Minis • A change in frequency suggests a presynaptic effect • A change in amplitude suggests a postsynaptic effect • These tests are not definitive; there are exceptions to these rules Analogies between Presynaptic Terminals and Somatodendritic Compartment Synaptic Terminal Somatodendritic Compartment 1. Output: quantal vesicle release, 1. Output: All-or-none action potential usually 0 or 1 2. Integration medium: membrane 2. Integration medium: [Ca2+] potential 3. Imaginary quantity: “Release 3. Imaginary quantity: “Instantaneous Probability” Firing Rate” 4. Spontaneous release 4. Spontaneous action potentials 5. Inputs: action potential, synaptic 5. Inputs: synaptic neurotransmission, neurotransmission, voltage- voltage-regulated ion channels regulated ion channels Synaptic Integration • Synaptic Integration: The process by which multiple synaptic potentials sum together within one postsynaptic neuron • This occurs in the