neuro - synaptic transmission
TRANSCRIPT
“Synaptic Transmission” 1-4-10 Dr. Clare Bergson
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Synaptic Transmission (These notes supplement the information I will present in my lecture, as well as that found in “Chapter 8: Synaptic Transmission between Neurons” in the textbook by J. Nolte.) From an evolutionary perspective, we humans can attribute our vastly superior level of intelligence, range of behaviors and flexibility, and hence our domination of the animal kingdom to the high level of synaptic connectivity in the human brain. The chemical synapse is the hub of neuronal connectivity in the CNS. -This class will address the following topics in what we currently know about synaptic transmission. 1) What is a neuronal synapse, and how are pre- and postsynaptic membranes and proteins organized to facilitate rapid and efficient communication betweens neurons? 2) What happens when an action potential invades a synapse, and what role does Ca+ entry, synaptic vesicles, and SNARE proteins play in regulating transmitter release? 3) Neurotransmitters and receptors in the CNS: differences in the kinetics and types of ligand gated ion channel and G-protein coupled receptor-mediated responses. 4) Termination of transmission: Transporters, degradative enzymes, and glia. 5) Diseases involving a disruption in synaptic transmission. Vesicles and synaptic transmission The idea that chemicals get released from nerve endings comes from studies of the neuromuscular junction (NMJ) in the 1940’s.The best studies chemical synapse is the NMJ. This is the site where peripheral neurons innervate muscle. The NMJ is also typical of a chemical synapse in the CNS in that the nerve terminal at the end of the axon has a specialized pouch like morphology where the axon is thicker. Also, on the postsynaptic side (a muscle cell in the case of the NMJ), ligand gated receptors for acetylcholine (nicotinic receptors) clustered for efficient signal transmission. This part of the muscle is called the ‘endplate’ [endplate because a saucerlike appearance where axon elaborates terminals], - Katz’ work on frog motor neuron stimulation of muscle contractions lead to the discovery of ‘endplate’ potentials (EPPs) or transient depolarization in membrane potential in the muscle. They also found that the plant toxin curare blocked the muscle responses. D-curarine is a competitive antagonist at nicotinic receptors, and is used as anesthesia in some surgeries to relax skeletal muscle. -Katz et al., also noticed smaller deflections in traces of electrical activity from muscle that looked like EPPs even without stimulating the axon. These deflections were called ‘spontaneous’ and because scaled down in size (< 1mV whereas EPPs are ~ 40-50 mV), called miniature EPPs or mini’s. The EPP size was much less than needed for threshold for postsynaptic action potential or contraction. But like the EPP’s the mini EPPs were sensitive to curare, but were observed even calcium free media.
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-Studies in low Ca++ showed that the evoked EPPs are about the same size as spontaneous mEPPs. Interestingly, saw a frequency distribution that showed the size of the EPP varied in an integral fashion (i.e., responses were 1, 2, 3 times the unit size). The unit-sized responses were given the name quanta, and one quanta was proposed to evoke a response <1 mV Electron microscopic studies of the NMJ showed membrane bound organelles in the nerve terminal. Biochemists purified these vesicles and found they were filled with acetylcholine (Ach). These are now called ‘synaptic vesicles.’ The vertebrate-specific toxin from black widow spider α -latrotoxin dumps all the synaptic vesicles (even in Ca++ free media). Years of study by EM’s of pre-synaptic terminals, and neurotransmission yielded the following general principles: 1) nerve terminal contains multiple synaptic vesicles, and multiple types of synaptic vesicles, 2) some vesicles are close to synapse, whereas as some removed from synapse, and 3) the synaptic vesicle might be the quanta or indivisible packet or sac of neurotransmitter released. Packaging of neurotransmitters into vesicles In addition to acetylcholine, neurotransmitters like glutamate, GABA, dopamine, norepinephrine and serotonin, as well as neuropeptides like NPY, vasopressin, oxytocin, melanocortin or the opiates are also packaged in synaptic vesicles, and are found in axonal boutons. Not all vesicles are alike. There are at least two varieties: small clear vesicles and large dense core vesicles (LDCVs). The LDCVs are not necessarily near the synapse ‘active zone’, whereas at least a fraction of small clear vesicles appear to be docked at the synapse proper. GABA, acetylcholine and glutamate are in clear vesicles whereas neuropeptides tend to be in LDCVs. Monoamines can be in either type depending on cell type. Nerve terminals can contain both clear core and LDCVs. When this happens the terminal is said to release co-transmitters. The concentration of Ach in a synaptic vesicle at the NMJ is about 100 mM or ~ 10, 000 molecules of Ach per vesicle based on size. How does so much transmitter get squeezed into a vesicle? For small molecule transmitters and monoamines, this is the job of proteins called transporters that pump neurotransmitter into vesicle against a concentration gradient using energy in the form of electrochemical gradient of co-transported ions. But peptide transmitters like ACTH, melanocortin, and the enkephalins, are synthesized and packaged into DCVs in the cell body, these DCVs are in turn transported along microtubular cytoskeleton to the terminal by motor proteins like kinesin that uses ATP (sometimes up to 400 mm/day). In contrast, small molecule transmitters are synthesized from precursors, and pumped into vesicle in the axon terminal. The enzymes for converting precursors to neurotransmitters are transported down the axon by microtubules. The transport of these enzymes and precursors is (~100 X) slower than for the DCVs.
“Synaptic Transmission” 1-4-10 Dr. Clare Bergson
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Dynamics of synaptic vesicle release Evoked release of neurotransmitter requires a rise in presynaptic Ca2+. This Ca2+ rise comes in from extracellular sources via voltage sensitive Ca2+ channels that are situated in the plasma membrane, some are located in the active zone where docked vesicles are released. Indeed, Ca++ channels in presynaptic terminal are a major determinant in evoked release of a bolus of synaptic vesicles by an action potential (as opposed to spontaneous release of a much smaller number of synaptic vesicles in the absence of an action potential invading the bouton). Presynaptic Ca2+ channels are mainly of the P/Q and N types, they can be modulated by G proteins resulting from GPCR stimulation as well as various kinases and phosphatases. The opening of Ca2+ channels in presynaptic terminal following AP invasion of bouton is a very fast event, i.e., the channels open quickly (0.1 ms) during peak action potential. As voltage decreases during descending phase of AP, there is a greater increase in Ca2+ influx via the channels. The local increase in Ca2+ in these domains around the channel might be 1000 fold. So, the Ca++ concentration might increase from ~ 200 nM to >/ 200 microM. Vesicles are located near Ca2+ channels are released sooner. The role of Ca++ in release of synaptic vesicles was figured out by injecting Ca2+, or Ca2+ chelator like EDTA. The Ca++ acts over short distances, 10’s of nanometers, and within v. little time (~ .2 msec). DCVs get released with stronger depolarizations due to more global increase in Ca++ throughout the terminal (or due to opening of channels further removed from active zone that have a higher threshold for opening, e.g., P and Q type channels). There are two well known disorders associated with presynaptic Ca2+ channels LEMS and FHM. Lambert-Eaton Myesthenic Syndrome (LEMS) is associated with certain cancers and arises from production of autoantibodies against P/Q type voltage gated Ca2+ channels. LEMS results in reduced evoked Ach release and failure in neuromuscular transmission. Seen as reduced evoked end plate potentials, muscle weakness and fatigue (but the amplitude of the spontaneous MEPP is normal). LEMS can be treated with immunosuppressant drugs and plasma exchange. Another is Familial hemiplegic migraine (FHM), a monogenic type of inherited migraine caused by mutations in the gene for the pore-forming subunit of P/Q-type Ca++ channels. Studies suggest the mutations increase open probability of the channel and increased probability of glutamate release, so lead to increased strength of excitatory transmission due to enhanced action-potential evoked Ca2+ influx. It is estimated that at the ‘active zone’ of the typical glutamatergic synapse in the CNS that there are ~ 2 to 20 vesicles in a ‘fusion ready’ state, i.e., they are also called ‘docked’ or ‘pre-docked’ at the presynaptic membrane. There is good evidence for an organizing structure for the docking of synaptic vesicles at ‘ribbon’ synapses. Ribbon synapses are an interesting variation on the typical central excitatory synapse, seen mostly in sensory neurons. Vesicles tethered to the ribbon proved a pool for sustained release that is ~5X greater than docked pool available for fast release.
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The molecular machinery of vesicle fusion Release of neurotransmitter from synaptic vesicles into the cleft requires fusion of docked vesicles with the plasma membrane. This fusion is a Ca2+ dependent process involving molecular machinery that is pre-assembled. Somehow Ca2+ influx triggers membrane fusion. The machinery is made of SNARE proteins which mediate membrane fusion in a wide variety of cells, not only neurons. SNARE proteins form complexes that bridge the donor and acceptor membrane. They do this by forming molecular zippers involving a 4-stranded coil-coil domains. The formation of these coil/coils in the zippers is thought to release enough energy to drive the 2 membranes together. Some SNARE proteins found at synapses are the targets of clostridial toxins like botulinin toxin and tetanus toxin. Synaptotagmin, a synaptic protein that binds Ca++ as well as SNARES and phospholipids is thought to facilitate membrane fusion. Synapaptotagmin binds PIP2, a phospholipid enriched in the plasma membrane via a C2 domain. The C2 domain is proposed to bind PIP2 in a Ca++ dependent fashion. The Ca2+ sensor has low affinity, so only a fraction of pool is released. Different isoforms of synaptotagmin are also found on LDCVs as well as synaptic vesicles. Exocytosis of synaptic vesicles is followed by rapid endocytosis of membrane and membrane proteins. Synaptic vesicle release is probabilistic, not a certainty. Many more vesicles are docked than are released. The reserve pool is typically 5-10x the size of the released pool. The Ca++ responsiveness of vesicles can vary, number of releasable vesicles can vary, Ca++ channel dynamics and magnitude of Ca++ influx can vary, as can the shape of action potential. Synaptic transmission is also highly regulated by G proteins, kinases and phosphatases. Ligand-Gated and G-protein coupled Postsynaptic Receptors The response of a neuron is a function of the type and number of receptors expressed. About half the synapses in the brain are excitatory, 30-40% inhibitory, and the rest involve small molecular or peptide transmitter. The binding of neurotransmitter to ligand gated ion channel (LGIC) receptors open ion channels in postsynaptic membrane. Excitatory transmitters, like glutamate, aspartate and acetylcholine open channels that permit the influx of positive ions like Na+ or Ca++, whereas inhibitory transmitters like GABA or glycine gate negatively charged Cl- ions. The ion fluxes change the membrane potential of the postsynaptic cell. In contrast, G-protein coupled receptors (GPCRs) accomplish this effect on postsynaptic membrane hyperpolarization or depolarization via 2nd messenger or G-protein mediated modulatory effects on ion channels. The structure of the pore forming unit of LGICs is similar to that of a variety of classes of voltage gated ion channels. LGIC contain multiple sites for regulation by second messengers.
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LGICs mediate rapid poststynatpic effects, with changes in membrane potential detected within milliseconds of an action potential invading the presynatpic terminal. The postsynaptic responses mediated by LGICs might only last only for 10s of millisecs, too. Ligands unbind quickly due to clearance mechanisms (transporters, degradative enzymes). LCIC numbers influence size of the post synaptic responses, along with other factors (i.e., channel open time, desensitization time). LGIC are also typically clustered at the synapses via interactions with synaptic proteins that are somehow tethered to synapse. AMPA and NMDA receptors are the main excitatory postsynaptic LGICs in the CNS. They play distinct roles at excitatory synapse, with both contributing to the postsynaptic potential. That is, the excitatory postsynaptic potential is usually multi-component. AMPA receptors open in a ligand dependent fashion whereas NMDA receptors also require the membrane to be depolarized before opening. At resting membrane potentials, the pore of the NMDA receptor is blocked by Mg2+ ions. Depolarization (usually through AMPA receptor stimulation) is necessary to remove the Mg2+ block. Another interesting feature of NMDA receptors is that glycine or D-serine is required as a co-agonist. Glia are a source of D-serine, so glia play at least two roles in modulating excitatory transmission: release of D-serine and uptake of glutamate via glutamate transporters. The drug APV blocks NMDA receptors. While most of the current let in is via AMPA receptors, NMDA receptors let in Ca2+ which activates a variety of enzymes linked to synaptic potentiation. Additionally, NMDA receptors show a slower onset, and a longer lasting response. GPCRs have a 7 transmembrane structure related to that of bacterial rhodopsin. Natural and endogenous ligands that bind GPCR range from stimuli that activate sensory systems to esoteric peptides (such as orexins, kisspeptin), as well as the typical cast of synaptic transmitters in the brain including glutamate, GABA, DA, NE, 5HT. GPCRs stimulate heterotrimeric G-proteins, and activate a range of effectors. In contrast to LGICs, GPCRs tend to localized peri-synaptically. They have higher affinity for ligands, and their activation depends on rate of removal of neurotransmitter as well as amount of neurotransmitter released. Although GPCR/G protein complexes might be preformed, the onset of the signal is slow compared to that of LGICs. GPCR signaling is terminated in various ways including GTP hydrolysis, receptor endocytosis and sometimes receptor degradation. Effect of GPCR on channels (via liberated G-proteins) might be detected for 100s of msec or longer (via second messengers and 3rd tier of 2nd messenger activated signaling cascades). GPCRs directly modulate presynaptic Ca++ channels, postsynaptic K+ channels, as well as 2nd messenger systems via heterotrimeric G proteins. The CB1 cannabinoid receptor provides an interesting example of this type of presynaptic regulation as it is activated by a retrograde signaling. Shutting off synaptic transmission Terminating neurotransmission is accomplished in part by diffusion and reduced release or receptor desensitization. However, the bulk of this task is performed by neurotransmitter transporters and degradative enzymes. Most transporters are found on presynaptic terminals. However, transporters for glutamate are located on astrocytes as well as on presynaptic
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terminals. Glutamate transporters in glia are also important in recycling glutamate in the form of glutamine to the excitatory nerve terminal. The catecholaminergic transporters are targets for drugs of abuse, used in treating ADHD or depression, and/or to promote weight loss. Various neurological or mental disorders are associated with degradative enzymes for neurotransmitters include acetylcholine esterase (a drug target in myasthenia gravis), monoamine oxidase (violence, treatment of mental disorders), catechol o methyl transferase (DA). Synaptic Integration Dendritic integration: usually EPSPs are subthreshold, need many to generate an action potential at the axon hillock. Summation will depend on frequency of EPSPs (#APs/unit time) as well as distance from soma (but there are mechanisms in dendrite to correct for inputs distal to the soma). During summation postsynaptic membrane stores change in capacitance that next action potential adds to. Synaptic plasticity, e.g., synaptic potentiation or depression, are adaptive responses that are thought to underly learning and memory, or information storage in general. Plasticity can be influenced by both presynaptic and postsynaptic events. For example of presynaptic: terminals with high probability of release, but small pool of vesicles will be prone to depression. Synaptic depression can also be facilitated by postsynaptic mechanisms such as rapid receptor desensitization or removal from the synapse. In addition, whether a synapse can be potentiated or depressed is a function of previous history. So if pool of vesicles is exhausted due previous depolarization and to slow rececycling, the subsequent response is likely to be weaker, too. On the other hand, some stimuli which open NMDA receptors lead to insertion of AMPA receptors, and a strengthening of subsequent post-synaptic responses is detected.
STUDY GUIDE FOR SYNAPTIC TRANSMISSION - BERGSON BRAIN & BEHAVIOR Please be knowledgeable about the following: 1. What defines a synapse? How is a quanta defined? 2. What is the difference between dense core synaptic vesicles and small clear synaptic
vesicles? 3. What is the difference between the neuromuscular junction (NMJ) and other
synapses? 4. What is required for rapid neurotransmitter release after a presynaptic action
potential? Does neurotransmitter release occur after each action potential?. 5. Which neurotransmitter is responsible for synaptic inhibition in the forebrain? 6. How does clostridial neurotoxin block neurotransmitter release? 7. How is it possible that small decreases in calcium can produce large changes in
neurotransmitter release? 8. What are the mechanisms by which neurotransmitters are removed from the synaptic
cleft? 9. What is meant by “coincidence detection”? To which neurotransmitter does this
process apply and why? 10. How does the activation of NMDA receptors produce excitotoxicity and neuronal
death? 11. What are the two major classes of postsynaptic receptors? What are the differences
between these two classes? 12. What is the difference between “point-to-point” vs. “diffuse” synaptic transmission? 13. What is the pathophysiology seen in myastenia gravis? How does this manifest into
clinical symptoms of the illness?
Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
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Synaptic Transmission
Phase I: January 4, 2010Lecturer: Clare [email protected]
Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
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Ramon y Cajal
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SYNAPTIC
TRANSMISSION
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Chemical transmission at neuronal synapses
• Background• Tripartite System
– Presynaptic terminal• Transmitter synthesis• Transmitter release
– Postsynaptic response• Receptor diversity and function
– Glia• Regulation of transmission
• Transmitter removal• Adaptive synaptic responses
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Chemical Synapse
The synapse is the basis for point to point communication between nerve cells
(as well as nerve and muscles)
NMJMuscleMotor neuron
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Fatt and Katz (1952): Spontaneous mEPPs
Synaptic Release is ‘Quantal’
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**** in low Ca++-containing media
Physiological evidence for release of synaptic ‘quanta’*
*indivisible packet of neurotransmitter
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Robertson (1956)-1st EM of synaptic vesicles at the NMJ
Morphological evidence for synaptic ‘quanta’
Synaptic Vesicles•Membrane-bound
organelles•40-60 nm in size
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Are vesicles the basis of quanta? Ceccarelli, Hurlbut…..(1990)
α-latrotoxinFrog NMJ
α-latrotoxin dumps all the synaptic vesicles (even in Ca++ free media)
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Actual dataResults predicted from model
(or after treatment with neostigmine, an AchE inhibitor)
Myasthenia gravis: apparent effects on quantal size
Elm
quistet al., 1964
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Presynaptic ultrastructure• nerve terminals contain numerous
synaptic vesicles- not randomly distributed
• some vesicles are “docked” at an ‘active zone,’ others are held in ‘reserve’
• only vesicles that are already dockedcan release neurotransmitter quickly (the “readily-releasable pool”)
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Two types of synaptic vesicles
DENSE
CLEAR
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Smallclear core
vesicles
LDCV
Either
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Neurotransmitter packaging• neurotransmitter concentrated in
synaptic vesicles by active transport: vesicular transporters
• utilize pH or membrane potential• vesicles contain a very high
concentration of neurotransmitter• Peptides are usually packaged into
LDCVs in the cell body
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Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
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Co-Transmitters
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Calcium channel structure (α 1 subunit)
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Ca++ Channelopathies and Neurological Diseases
• Lambert-Eaton myasthenic syndrome (LEMS)– Auto-antibodies vs. P/Q-type Ca++ channels
• Familial hemiplegic migraine (FHM)– Mutations in the gene for the pore-forming
subunit of P/Q-type Ca++ channels lead to enhanced evoked Ca++ influx.
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Calcium influx triggers release (fusion) of docked vesicles
• release requires a very high, local [Ca++]– Rapid <0.5 msec,100-1000x increase
• Release is brief– Channels close– Ca++ diffuses away
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Calcium domains
‘Docked’
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‘Docked’ vesicles
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‘Docked’ vesicles at ribbon synapses
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What drives vesicle fusion?
• SNARE proteins on vesicles and on target plasma membrane
• Molecular machinery involved in membrane fusion events– Synaptobrevin (VAMP)=vSNARE– Syntaxin=tSNARE– SNAP25=tSNARE
• SNAREs are targets of clostridial toxins
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Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
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Before
After
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Synaptotagmin: a candidate Ca++ sensor
• binds Ca2+ with low affinity• located near Ca2+ channels• interacts with phospholipids
and SNARE proteins• found exclusively on synaptic vesicles• genetic ablation abolishes
evoked but not spontaneous release
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How does calcium trigger vesicle fusion?
Docked vesicles located near Ca++ channel vSynaptotagmin binds Ca++ and
translocates to plasma membrane
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The reliability of release can be modulated
• the probability of release can be decreased or increased by second messengers (G-proteins, cAMP)
• the probability of release can be decreased or increased by activity
• presynaptic inhibition• modulation can occur at several points
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Synaptic vesicles are recycled
~30 sec
Incomplete fusion Complete fusion
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Presynaptic summary:• an action potential invades a presynaptic
terminal, where some vesicles are already docked and waiting...
• calcium channels open, flood nearbyvesicles with a high concentration of Ca2+…
• Ca2+ ions bind a low affinity sensor, greatly increasing the probability of vesicle fusion/release...
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presynaptic summary (continued):• if vesicles fuse, these release a high
concentration of neurotransmitter…• calcium channels close very quickly as
the action potential repolarizes...• Ca2+ quickly diffuses away from vesicles
that are still docked, the probability of vesicle fusion returns to a low value...
• neurotransmitter concentration in the synaptic cleft falls quickly…
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Neurotransmitter release is probabilistic
• a docked vesicle may or may notfuse/release after an action potential
• calcium merely increases the probability that release will occur (transiently)
• synaptic reliability is determined in part by the number of releasable vesicles
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B. Synaptic depression-pool with high probabilityof release, but small pool,or slow vesicle recycling
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Short-term Plasticity
(altered reliability)=f[previous history, stimulation pattern]
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Postsynaptic receptors• Major classes of postsynaptic receptors:
– Ligand-gated ion channels (LGICs) – G-protein-coupled receptors (GPCRs)
• many ligands bind both classes• multiple receptors can be present at a
given synapse
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Point-to-point vs. diffuse “synaptic” transmission
• Point-to-point: rapid information transfer, directly alter firing (usually LGICs)
• Diffuse: slower modulatory actions, may or may not alter firing (usually GPCRs)
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LGIC
GPCR
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LGICs: general properties• structurally related to voltage-gated ion
channels; multiple subunits• divided into families of related channels• selective for monovalent cations (Na+,
K+) or anions (Cl-, HCO3-)
• a few are also permeable to Ca2+
• ligands usually small molecules
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LGIC structure
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LGICs: affinity
• LOW affininity for neurotransmitter (Kd in the micromolar range)– ligands unbind fairly quickly– must be close to the release site to
“see” a high concentration of ligand (are clustered at postsynaptic density)
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LGICs are clustered
NR1
GluR1
syn
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LGICs: kinetics• ligand binding (2 molecules) increases
probability of channel opening• LGIC open probability is raised for
2-20 ms following release, starting <1ms following release
• bind, open, close, open...close, unbind• can close persistently with ligand bound
(desensitize) if ligand persists
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LGICs: numbers• at CNS synapses, 10-100 LGICs open in
response to a single vesicle• receptor number may change rapidly• quantal PSPs are small (~0.1mV)• signal proportional to channels bound (no
amplification)
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Specific LGICs• glutamate receptors (GluRs)
– AMPA– NMDA
• GABAA receptors (GABA-Rs)• glycine receptors (GlyRs)• nicotinic Ach, 5HT3, ATP….
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NMDA receptors• a type of glutamate receptor• pore blocked by magnesium at
hyperpolarized potentials• can only open during depolarization
(‘coincidence detection’)• requires glycine or D-serine as co-agonist• pass calcium (fairly unique)• important for some types of plasticity
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NMDA Receptor Co-agonists
serine racemase
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LGICs: Clinical Significance• Glutamate receptors mediate
excitotoxicity (stroke, epilepsy)• GABAA receptors are sites of action of
benzodiazepines, barbiturates, anesthetics, ethanol
• nAch blockers for anesthesia– D-curarine
• targets of auto-immune disease
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GPCRs: general properties
• all related 7TM domain proteins• ligands diverse (small molecules,
peptides; odorants, light)• exert actions by coupling to
heterotrimeric G-proteins• activated G-proteins activate a large
number of downstream effectors
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GPCR Structure
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GPCRs: affinity
• HIGH affinity for ligands (Kd in nano-molar range)– remain bound by ligand for some time– so need not be located at a synapse– binding depends on distance from a
synapse, and number of vesicles released
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Receptor affinity
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GPCRs: kinetics
• time is required for multiple protein-protein interactions– onset is slow (10-100 ms)– peak is late (100 ms-seconds)
• action terminated by GTP hydrolysis• bound receptors can activate multiple
G-proteins, multiple effectors, large capacity for amplification/divergence
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0 2 0 0 4 0 0 6 0 0
G A B A B (G P C R )
G A B A A (L G IC )
T im e (m s )
Receptor kinetics
Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
5/31/2005
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GPCRs: effectors• voltage-gated calcium channels• K+ channels (open or close)• adenylate cyclase (cAMP)• phospholipase (IP3; DAG)• many others, incl. transcription factors• many effects of GPCRs do not change
membrane potential
Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
5/31/2005
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Specific GPCRs
• glutamate (metabotropic GluRs; mGluRs)
• GABAB
• muscarinic acetylcholine• dopamine, opiate, 5HT, adrenergic…...
Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
5/31/2005
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Copyright ©2009 American Physiological Society Kano, M. et al. Physiol. Rev. 89: 309-380 2009;
CB1 receptors and retrogradeendocannabinoid signaling
Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
5/31/2005
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GPCRs: clinical significance• targets (direct or indirect) of a huge list
of clinically useful drugs (too numerous to mention)– E.g., L-dopa for Parkinson’s Disease
• GPCRs important for “modulatory”actions
Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
5/31/2005
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• low affinity• located at synapse• fast/brief• no amplification• 1 signal (Vm)• small molecules• point-to-point
• high affinity• peri/extrasynaptic• slow/prolonged• amplification• divergent signals• small/large molecules• diffuse
LGICs GPCRs
Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
5/31/2005
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Termination of transmissionNeurotransmitter Removal
• removal of neurotransmitter from the synaptic cleft is accomplished in part by diffusion (amino acids)
• rapid sodium-dependent re-uptake keeps the resting concentration of NT low (transporters)
• enzymatic degradation is important for acetylcholine, ATP, and monoamines
Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
5/31/2005
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Catecholamine Transportersas Drug Targets
ADHD DepressionShort term weight loss
ADHD
Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
5/31/2005
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Copyright ©2008 American Physiological Society
Theodosis, D. T. et al. Physiol. Rev. 88: 983-1008 2008
Astrocytes are enriched in Glutamate Transporters
Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
5/31/2005
63
ALS and glutamate transport
(Glt-1)
Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
5/31/2005
64
Synaptic integration• “Unitary” EPSPs are usually
subthreshold• Neurons integrate many E and I inputs
from entire structure• Spatial and temporal summation• AP initiation in initial segment
Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
5/31/2005
65
Postsynaptic vs. Action Potentials
Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
5/31/2005
66
Distal events are filtered by dendrites
Chemical Signaling by CNS NeuronsClare Bergson, [email protected], 1-1926, CB3616
5/31/2005
67
Dendritic Integration of Synaptic Events