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Week beginningMonday 29 July 2013
Lecture 3
Synaptic Transmission
Lecturer: Dr Lucy [email protected]
Lundy: Chapter 2 (pp. 27-37) & Chapter 3 Kandel: Chapter 9 (pp. 189-195) Tortura: pdf on moodle
Reading
Lundy-Ekman. Neuroscience: Fundamentals for Rehabilitation, 4th Edition. W.B. Saunders Company, 2013.
Kandel et al. Principles of Neural Science, 5th Edition. McGraw Hill, 2012.
Tortura & Derrickson. Principles of anatomy and physiology, 13th
Synaptic Transmission◦ Neuromuscular Junction (Kandel)
Neurotransmitters Drug Actions
Overview
Be able to draw and label a typical synapse Know the processes involved in synaptic
transmission Understand the difference between EPSPs and
IPSPs Understand the processes involved at the
neuromuscular junction and how this is disrupted by myasthenia gravis
Have an appreciation of the major types of neurotransmitters
Know the processes by which drugs can affect synapses
Lecture Objectives
A synapse is the region of communication between two neurons or a neuron and its target cell (e.g., muscle fiber)
Action potentials cannot “jump” across this gap but instead release neurotransmitters into the synaptic cleft (gap)
This process is called synaptic transmission
Synaptic Transmission
It is at this level we are now looking – where one terminal button connects with a dendrite or soma
1. An AP arrives at the synaptic terminal of the presynaptic neuron
2. Voltage-gated Ca2+ channels open and calcium flows in to the cell (away from its concentration gradient)
3. The increase in concentration of Ca2+ triggers exocytosis of synaptic vesicles (containing neurotransmitter molecules). Vesicles merge with membrane and NTs are released into the synaptic cleft
Events at the Synapse
4. NT diffuse across cleft and bind to postsynaptic/neurotransmitter receptors
5. Binding of NT molecules to their receptors opens the channels and allows particular ions to cross the membrane (Na+ shown)
6. As ions flow through the open channels the resting membrane potential changes (in this case depolarizes the cell)
7. When the post-synaptic cell reaches threshold (at its axon hillock) an action potential is elicited
Events at the Synapse
8. Neurotransmitter is then released from its binding sites back into the synaptic cleft and the channels close
9. Through special channels in the presynaptic terminal membrane these NTs are taken back into the terminal button and repackaged into new vesicles and used again. A lovely little recycling story
NB: NTs are also “lost” from the synaptic cleft if they diffuse away from the synapse, or are inactivated by enzymatic degradation (so they either (1) make it home, (2) get lost, or (3) get eaten!!)
Reuptake
Local changes in ion concentration across the postsynaptic membrane.
Effect can be:◦ Local depolarization -> excitatory (EPSP) because the cell is
brought closer to threshold◦ Or local hyperpolarization -> inhibitory (IPSP) because the cell
is taken further from threshold Depends on the type of ion (+ or -) the open channel
allows diffusion of (positive ions will produce a depolarization, negative ions will produce a hyperpolarization)
The same neurotransmitter, however, can act on many different ion channels, and elicit EPSPs or IPSPs for this reason
Postsynaptic Potentials
Ion channel allows Na+ or Ca2+ into neuron (positively charged) causing depolarization – increasing possibility of an AP
E.g., neuromuscular junction (ACh/Na+)
Excitatory Postsynaptic Potentials
The ionotropic acetylcholine (ACh) receptor contains two binding sites for ACh and a cation channel. Binding of ACh to this receptor causes the cation channel to open. Opening the cation channel allows passage of the three most plentiful cations (Na+, K+ and Ca2+) through the postsynaptic cell membrane, but Na+ inflow is the greater than either Ca2+ inflow or K+ outflow and an excitatory postsynaptic potential (EPSP) is generated.
Excitatory Postsynaptic Potentials
Ion channel allows Cl- into neuron (or K+ out of neuron) causing hyperpolarization – decreasing possibility of an AP
E.g., benzodiazepines Summation
Inhibitory Postsynaptic Potentials
The ionotropic gamma aminobutyric acid (GABA) receptor contains two binding sites for GABA and a Cl- channel. Binding of GABA to this receptor causes the Cl- channel to open. Opening the Cl- channel allows a larger number of chloride ions to diffuse inward and an inhibiting postsynaptic potential (IPSP) is generated.
Inhibitory Postsynaptic Potentials
Summation is the process by which potentials add together (to collectively bring a cell to its threshold for action potential… or not)
Spatial summation: summation of postsynaptic potentials occurring at different locations in the postsynaptic cell at the same time
Temporal summation: summation of postsynaptic potentials occurring in the same location at different times
Summation
NTs released into synaptic cleft -> bind to postsynaptic receptor
These receptors usually named after NT that binds to them◦ Receptors that bind GABA are called GABA
receptors Most NTs can bind to several different types
of receptors Thus, effect of a NT is based not on the
chemical itself, but on the type of receptor to which it binds
Types of Receptors and NTs
Neurotransmitters
1. Acetylcholine (ACh)◦ PNS; motor neurons use ACh to elicit fast-acting
effects on muscle fibers◦ Neurotransmitter involved at neuromuscular
junction
(we will cover the neuromuscular junction and myasthenia gravis next and then return to other types of NTs)
Major Neurotransmitters
Junction between somatic motor neuron and skeletal muscle fiber
(Where synaptic transmission first studied/understood)
Neuromuscular Junction (EPSP)
End-plate: region where neuron innervates muscle
Neuron splits into several terminal buttons filled with ACh
Each button positioned over junctional fold (where ACh receptors are located)
Junctional fold is deep groove in the motor end plate provide large surface area
1. Arrival of action potential stimulates voltage-gated Ca2+ channels to open and Ca2+ flows inward. This stimulates the vesicles to undergo exocytosis, expelling ACh neurotransmitter into the synaptic cleft
2. Binding of two molecules of ACh on the motor end-plate opens an ion channel allowing Na+ to flow across the membrane
3. The inflow of Na+ makes the inside of the muscle fiber more positively charged triggering an AP. This propagates along the sarcolemma into the system of T tubules which causes the sarcoplasmic reticulum to release stored Ca2+ and the muscle fiber contracts
4. The ACh is then broken down by an enzyme
Process at the NMJ
Neuromuscular Junction
Acetylcholine (ACh)◦ PNS; motor neurons use ACh to elicit fast-acting effects on
muscle fibers. ◦ Neurotransmitter involved at neuromuscular junction.
Myasthenia gravis: disease that destroys ACh receptors
Major Neurotransmitters
Normally there are a large number of ACh receptor-channels at end-plate to ensure signaling occurs at max strength
Myasthenia gravis is an autoimmune disease where antibodies inappropriately produce antibodies that bind to and block some ACh receptor-channels
This decreases the number of functional ACh receptor-channels and has the effect of weakening the muscles
Myasthenia gravis
It is thought that thymic abnormalities cause the disorder because 75% of MG sufferers have hyperplasia or tumors of the thymus
As disease progresses more and more ACH receptors are lost and muscles become weaker and weaker, fatigue more easily and may cease to function
Muscles of face and neck most often affected (e.g., eye muscles producing double vision (diplopia), throat muscles causing difficulty in swallowing, chewing, talking)
Death may result from paralysis of respiratory system
Myasthenia gravis
Amino Acid transmitters fast-acting 2. Glutamate – major excitatory
neurotransmitter involved in learning & development. Can contribute to neuronal death (next lecture)
3. GABA – major inhibitory neurotransmitter CNS (interneurons)
4. Glycine – major inhibitory neurotransmitter in brain stem and spinal cord◦ Both GABA & Glycine prevent excessive neural
activity. Low levels -> seizures, contractions, anxiety
Major Neurotransmitters
Why are we starting at 2?? 1. Ach
Amines (slow-acting transmitters) 5. Dopamine
◦ Affects motor activity (Parkinson’s), cognition (Schizophrenia), behaviour.
◦ Pleasure/reward system (addiction) 6. Norepinephrine (noradrenaline)
◦ Involved in vigilance and sleep, “fight-or-flight” reaction to stress
◦ Overactivity -> panic (PTSD) 7. Serotonin
◦ Affects mood, perception of pain, arousal◦ Depression (Prozac SSRI)
Major Neurotransmitters
Peptides can act as neurotransmitters or neuromodulators
8. Substance P◦ Stimulates nerve endings when tissue injured◦ Involved in pain syndromes where innocuous stimuli
perceived as painful◦ Modulates immune and neural activity during stress
9. Galanin◦ Role in control of food intake, mood, alertness, pain
perception◦ Expressed in hypothalamus, cortex, brainstem, spinal cord,
gut◦ Inhibits insulin release through autonomic neurons that
innervate the pancreas.
Major Neurotransmitters
1. Stimulate the release of neurotransmitters2. Inhibit the release of neurotransmitters3. Stimulate postsynaptic receptors4. Inhibit postsynaptic receptors5. Inhibit reuptake
Effects of Drugs on Synaptic Transmission
Black widow spider venom stimulates release of ACh Acetylcholine (ACh) - Secreted by neurons involved in muscle
action – neuromuscular junction Na+ ions involved Leads to rapid, uncontrolled firing of postsynaptic cells, leading
to failure of functioning Numbness, muscle pain, cramps, sweating, salivation, death in
infants and elderly
1. Stimulate release of NTs
Spider venom
ACh
Na+ ions
Botulinum toxin (Botox) prevents the release of ACh neurotransmitters and therefore, prevents muscles contracting
Acetylcholine (ACh) - Secreted by neurons involved in muscle action – neuromuscular junction
Na+ ions involved Botox inhibits release of ACh
neurotransmitter Failure of facial muscles to
contract and cause wrinkles!!
2. Inhibit release of NTs
Botox
Benzodiazepines stimulate GABAA receptors by binding to them, causing them to stay open for longer, allowing more Cl- ions to enter cell
(GABA is the neurotransmitter that binds to GABAA receptors, which let Cl- ions pass through
These receptors serve to inhibit APs by further hyperpolarizing the postsynaptic cell
3. Stimulate receptors
Benzo
GABAA receptor-channel
Curare blocks ACh receptors at the neuromuscular junction. Because these are the receptors on muscles, curare, like botox, causes paralysis, but much faster…and no lack of consciousness! Remember bath scene in movie “What Lies Beneath”? That was curare.
Na+ ions involved Used by hunters on spear tips to kill animals (in jungles of
Peru, etc.)
4. Inhibit receptors
http://www.youtube.com/watch?v=irr4b40Ok7E&list=PL84629EA1FA286907
curare
Cocaine inhibits reuptake Dopamine is an
excitatory neurotransmitter for dopamine receptors
Na+ ions involved Causing overstimulation
of Na+ ions in synaptic cleft
Postsynaptic cell continues to fire
5. Inhibit reuptake
dopamine
Na+ ions
NT Ion Primary Effects
Drugs Effects of Drugs
ACh Na+ Excitatory Black widow spider venom
1. Stimulates release of ACh
ACh Na+ Excitatory Botulinum toxin
2. Inhibits release of ACh
GABA Cl- Inhibitory Benzodiazepine
3. Stimulates GABAA receptor
ACh Na+ Excitatory Curare 4. Inhibits ACh receptors
Dopamine Na+ Excitatory Cocaine 5. Inhibits reuptake
Summary of Drug Effects
