Week beginningMonday 29 July 2013

Lecture 3

Synaptic Transmission

Lecturer: Dr Lucy Patstonlpatston@unitec.ac.nz

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

http://www.google.co.nz/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&docid=zwenEcL0FbG-UM&tbnid=aJ5skW5NNKxf7M:&ved=0CAUQjRw&url=http://www.dallah-hospital.com/en/NewsEventsArchive.aspx?PageId=3&dateFrom=12A1A2010&dateTo=12A31A2010&ei=-gsgUfbSE4n1lAWUp4HYDg&bvm=bv.42553238,d.dGI&psig=AFQjCNH6rA73mEx02XpqscSlQWYbUsPL4Q&ust=1361141054683894

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