Neurophysiology (Part II): Synapses and Receptors PDF

Neurophysiology (part II): Synapses and Receptors When the action potential gets down to the axon terminal, what happens? Here’s where the synapse and neurotransmitters come in Synaptic Transmission Action potential originates at axon hillock; propagates along th...

Neurophysiology (part II): Synapses and Receptors When the action potential gets down to the axon terminal, what happens? Here’s where the synapse and neurotransmitters come in Synaptic Transmission Action potential originates at axon hillock; propagates along the presynaptic membrane of the axon (myelin sheath, nodes of ranvier); reaches the axon terminal Action potential ‘arrives’ to the axon terminal; causes depolarization (more positive) in the terminal Synapse Synapse ~20-50nm wide synaptic cleft Terminal contains mitochondria, vesicles, and proteins. Small vesicles contain small molecule neurotransmitters Made in cytoplasm, packaged by Golgi apparatus ~20-30 nm Can also be made by recycled membrane in terminal Large dense-core vesicles contain peptides (more on this later on…) Made in soma by ribosomes; transported to terminal via microtubules Synapse Post synaptic density (PSD) Filaments & other proteins traverse the synaptic cleft; variety of functions, including: synapse formation align pre- and postsynaptic sides mediate synaptic function Synaptic Transmission Action potential ‘arrives’ to the axon terminal; causes depolarization (more positive) in the terminal Terminal has vesicles filled with neurotransmitters, waiting to be released Pre-synaptic membrane is lined with voltage-gated calcium channels; in response to the depolarization, these channels open and Ca2+ ions enters pre-synaptic terminal Calcium promotes exocytosis (release neurotransmitters into synaptic cleft) Synaptic Transmission Exocytosis: influx of Ca2+ causes synaptic vesicles to fuse with presynaptic membrane and release neurotransmitter into the cleft; mediated by specialized proteins SNAREs (act like tethers) and synaptotagmin (act like sensor tags) Synaptic Transmission Calcium influx causes vesicles already fused with membrane (“docked” or “release-ready” vesicles) to break open and “spill” neurotransmitter into synaptic cleft  A photograph from an electron microscope, showing a cross section of a synapse (frog NMJ) Synaptic Transmission ? protein ? protein ? protein Synaptic Transmission Synaptic Transmission The fate of synaptic vesicles that have released neurotransmitter into the synaptic cleft. Kiss and run: vesicle releases neurotransmitter, reseals and leaves Merge and recycle: vesicle fuses with and is incorporated into presynaptic membrane Bulk endocytosis: formation of new vesicles Synaptic Transmission Types of Neurotransmitters There can be small- and large-molecule transmitters in the same terminal button; coexistence Small-molecule transmitters are usually released each time an action potential arrives (organic cation) at the terminal Large-molecule transmitters are released gradually in response to multiple action potentials More to come in Chapter 4: Neurotransmitters Synaptic Transmission Neurotransmitters enter synaptic cleft and many bind to receptors: Specialized proteins in the cell membrane Neurotransmitters interact with receptors to affect the postsynaptic cell (primarily via ion flow; EPSPs, IPSPs) Synaptic Transmission – Receptors Ligands fit receptors exactly and activate or block them Lock & key model Neurotransmitters are ligands (i.e., the key) Receptor are the lock Neurotransmitter 1 Receptor-Ligand complex Receptor Neurotransmitter 2 Synaptic Transmission – Receptors Ionotropic receptors (aka ligand-gated ion channel) open when bound by a transmitter; allow ions to flow across the membrane, changing the charge of the cell membrane Metabotropic receptors (aka G-protein-coupled receptors) relay information into the cell when bound by a transmitter; use a series of proteins to cause a cascade of effects Ionotropic receptors Metabotropic receptor G proteins open ion channels to change membrane potential May also activate other chemicals called the second messenger (first messenger is neurotransmitter) to amplify effects of the G protein Don’t worry about any of these specifics … Just appreciate how much is going on!! Synaptic Transmission – Ionotropic Receptors Ligand-gated ion channels Happens quick (~1 ms) Short lasting effects (~5 ms) Most excitatory (i.e., depolarizing) ionotropic synapses use glutamate Most inhibitory (i.e., hyperpolarizing) ionotropic synapses use GABA Good for visual or auditory information Synaptic Transmission – Metabotropic Receptors Longer to onset (30 ms+) Longer lasting effects (several seconds to minutes) Wide variety of neurotransmitters (dopamine, norepinepherine, seratonin, GABA and glutamate) Good for enduring effects like taste, smell or pain 2nd messengers Open/close ion channel neurotransmitter –and/or– G-protein Alter gene expression Synaptic Transmission – Metabotropic Receptors Longer to onset (30 ms+) Longer lasting effects (several seconds to minutes) Wide variety of neurotransmitters (dopamine, norepinepherine, seratonin, GABA and glutamate) Good for enduring effects like taste, smell or pain Synaptic Transmission – Receptors Ionotropic receptors (aka ligand-gated ion channel) open when bound by a transmitter; allow ions to flow across the membrane, changing the charge of the cell membrane Metabotropic receptors (aka G-protein-coupled receptors) relay information into the cell when bound by a transmitter; use a series of proteins to cause a cascade of effects Synaptic Transmission –Receptors What happens next depends on the receptor 1. Ligand binds to receptor 2. Activates the receptor 3. The receptor may be excitatory or inhibitory (based on the effects on the post-synaptic neuron) Excitatory Post-Synaptic Potential: EPSP Depolarizes the neuron Makes the inside less negative Inhibitory Post-Synaptic Potential: IPSP Hyperpolarizes the neuron Makes inside more negative If neuron reaches the threshold potential (via temporal and /orspatial summation), it will fire action potential Synaptic Transmission – Receptors Ionic movements during postsynaptic potentials cause inhibition (hyperpolarization) or excitation (depolarization) of the postsynaptic cell Selective neurotransmitter-dependent (i.e., ligand-gated) ion channels: sodium, potassium, chloride, and calcium -or- Influx of K+ causes depolarization (EPSP) Synaptic Transmission – Receptors (example) Cholinergic ionic receptors respond to acetylcholine (Ach) Otto Loewi (Nobel Prize, 1936)’s discovery of neurotransmitters Synaptic Transmission – Receptors (example) Cholinergic ionic receptors Remember the receptor-ligand lock and key analogy? respond to acetylcholine (ACh) Subtypes of ACh receptors Endogenous which also respond to different Exogenous agonist Antagonist ligand (Ach) (muscarine) (curare) ligands (nicotine & muscarine) Nicotinic receptors found at autonomic ganglia and in neuromuscular junctions of voluntary muscles Most Ach receptors in the brain are muscarinic (also ACh musc R ACh musc R ACh musc R found on organs innervated by parasympathetic nerves) Muscarinic and nicotinic Endogenous ligand: made by the body; neurotransmitter or synapses can be excitatory hormone (open channels for Na+ and K+) or inhibitory (open channels for Exogenous ligand: comes from elsewhere – plant, lab-made Cl−); at least four subtypes of Agonists: mimic the neurotransmitter (nicotine, muscarine) Ach synapses Antagonist: interferes with the neurotransmitter; blocks activation of the receptor (curare, bungarotoxin) Synaptic Transmission – Receptors The number of receptors in cells can vary: Daily in adulthood During development With drug use Up-regulation is an increase in the number of receptors Down-regulation is a decrease in the number of receptors Synaptic Transmission Neurotransmitters only bind to receptors for a short time and need a way to be removed from synaptic cleft: Degradation: The neurotransmitter is broken apart. Diffusion: The neurotransmitter moves down the concentration gradient and out of the synapse. Reuptake: Neurotransmitter is transported back into the original cell. Synaptic Transmission – Clean up 1) Enzymatic degradation Enzymes rapidly break down Component molecules can be re-used E.g., destruction of acetylcholine (ACh) by acetylcholinesterase (AChE) 2) Diffusion Neuropeptides can diffuse away Absorbed by glial cells (e.g., Glutamate, GABA) 3) Reuptake into pre-synaptic neuron Special transporter proteins in membrane Synaptic Transmission Autoreceptors on presynaptic membrane bind transmitters; inform the cell about transmitter concentration in the cleft, which can be adjusted Retrograde Synapses Gases (e.g., nitric oxide; NO) diffuses out of postsynaptic cell and impacts presynaptic cell Typically signals presynaptic cell to release transmitter Can signal glial cell to produce more gas Nondirected Synapses Most synapses that are discussed are directed synapses (synapses where the site of release and the target site are close together; synaptic clefts) There are also nondirected synapses: some presynaptic axons have a string-of-beads appearance and the neurotransmitter is widely dispersed from each bead to many targets in the general area This arrangement is common for monoamine neurotransmitters. Neurotransmitter diffuse out of axonal varicosities (windows) along axon branches and impact neurons in the vicinity Electrical synapses – gap junctions Action potential jumps directly to postsynaptic region without being transformed into a chemical signal Gap junctions between neurons: membranes meet & almost touch Membranes contain large channels (connexons) for ions to diffuse from one cell to another; thus, change in membrane potential in one → change membrane potential in other; with no time delay Typically dendrodentric, can also be axosomatic and axodendritic, also glial (e.g., tripartite synapses allow astrocytes to synchronize activity between groups of neurons) For escape behaviors in invertebrates, movement of eyes Faster than chemical Potential role of spread of synchronous brain activity in seizures synapses Electrical synapses – gap junctions Gap junctions connect the cytoplasm of two adjacent cells. In the mammalian brain, there are many gap junctions between glial cells, between neurons, and between neurons and glial cells. Electrical synapses – gap junctions Elements of reticular theory are now further appreciated thanks to gap junctions Gap junctions can be dynamically opened and closed to synchronize swaths of neurons Chemical (local) & electrical (network) synapses play a role in neural function Neural circuits/networks Neurons and synapses combine to make circuits Neural chain: simple series of neurons E.g., the knee-jerk reflex consists of a sensory neuron, a synapse, and a motor neuron Extremely fast: large myelinated axons, sensory cells synapse directly onto motor neurons, ionotropic synapses. Neural circuits/networks The visual system can be represented as a neural chain, but is actually more complex. Convergence: many cells send signals to one cell Divergence: one cell sends signals to many cells 100M light receptors → 1M axons → Billions cortical neurons Review Sequence of synaptic transmission: 1. Action potential arrives at axon terminal 2. Voltage-gated calcium channels open and Ca2+ ions enter 3. Synaptic vesicles fuse with membrane and release transmitter into the cleft 4. Transmitter crosses the cleft and binds to postsynaptic receptors, which opens ion channels 5. Ion flow creates a local EPSP or IPSP in the postsynaptic neuron 6. Transmitter is inactivated (degraded) by enzymes or removed by transporters—so transmission is brief (and meaningful) 7. Transmitter may activate presynaptic autoreceptors, decreasing its release Groups! Review Review Q. What causes threshold to be reached at the axon hillock? A. Synaptic activity on the neuron itself. Excitatory Post-Synaptic Potential: EPSP Depolarizes the neuron, makes the inside less negative Inhibitory Post-Synaptic Potential: IPSP Hyperpolarizes the neuron, makes inside more negative If neuron reaches the threshold potential, it will fire Review