Week 3 lecture 3 neurotransmission PDF

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Lecture 3 - Brain and Behaviour...

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Lecture 3 Neurotransmission How Do Neurons Transmit Information (Neuronal Transmission I) – Resting and Action Potentials Voltage  the difference in charge between two points. Current  the rate at which charge is flowing.

Structure of a Neuron Dendrites: -

Dendron = tree. Recipient of information from other neurons. Large receptive field.

Soma: -

Cell body. Contains machinery that controls processing in the cell and integrates information. Nucleus is within the soma.

Axon: -

Carries information (action potential) from the soma to the terminal boutons and hence to other cells. Can branch to contact multiple neurones. Also called synaptic transmitters.

Terminal Boutons (buttons): -

Found at the end of the axon, location of the synapse, communication point with other neurons.

Neuronal Membrane What surrounds the neuron is the membrane. It keeps certain substances out; this is how specific information can reach the neuron. Boundary of soma, dendrites, axon and terminal boutons. Separates the extracellular environment from the intracellular environment. Membrane: Lipid bilayer (5nm) -

Hydrophilic head, hydrophobic tails. Protein Structures: -

Detect substances outside the cell.

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Allow access of certain substances into the cell (gated: chemical or electrical). Cytoskeletal.

Resting Potential Properties of the Neurons that are Important for Within Neuron Communication Membrane potential  electrical charge across the membrane. At rest  difference between the inside and the outside of neurons is approximately 6570mV (millivolts). At rest  inside is more negatively charged than the outside (inside of the membrane is -65 to -70 mV).

-ve

+ve

Voltmeter (measures flow and strength of electrical voltage, records difference in electrical potential between two bodies.

Microelectrode.

Squid axon in sea water.

Hodgkin & Huxley, 1930

What causes there to be a membrane potential? The movement of particles across a membrane due to two forces. Force of diffusion – molecules move from an area of high concentration to an area of low concentration. Salt (NaCl) splits into particles: -

Na+ Cl-

Force of electrostatic pressure: -

Particles with a similar charge repel. Particles with an opposite charge attract.

P+ Cations (Na+) N- Anions (Cl-).

The Equilibrium Potential 1) P+ ions move across membrane by diffusion force (high concentration to low concentration). 2) As P+ ions move there is an increase in electrical potential across the membrane (i.e. more +ive on one side and more -ive on the other). 3) Eventually, a point is reached when the diffusion force = electrostatic force. Equilibrium potential (outward movement = inward movement) is achieved. - Initial concentration difference important  high conc. = large equilibrium potential (vice versa). - Very few ions need to move to achieve this.

What Causes there to be a Membrane Potential?

Organic anions make charge inside negative. Occurs as there is a separation of charge across the membrane.

The Resting Membrane Potential: -65 to -70mV

Every neuron has resting/leak channels. At rest have 40 times more K+ channels open than Na+. More chance of potassium diffusing across membrane than sodium – more potassium channels than sodium.

The Nernst Equation The equilibrium potential can be calculated for any ion using the Nernst equation. It is determined by the outside concentration of ions, and the inside concentration of ions. If bigger concentration outside than inside = positive equilibrium potential. If bigger concentration inside than outside = negative equilibrium potential. The Resting Membrane Potential More potassium ion channels than sodium, so potassium can travel more easily from inside to outside and bring the equilibrium potential towards -85mV. Sodium also has some channels, and so some comes inside the cell, so it brings the resting potential to -65 to -70mV.

Sodium-Potassium Pump Sodium-Potassium pump maintains the ionic concentration gradients (Na+ and K+) across the membrane and therefore resting membrane potential. Trying to restore the original gradient as much as possible and compensate for the sodium and potassium leaks. Potassium comes back in, sodium is trying to go back out.

Part II: Action Potential The action potential Electrical nerve impulse. Allows communication within the neuron along the axon. Generated at axon hillock. Generated either by the summation of converging inputs from the dendrites or by electrical stimulation (experimentally).

Hyperpolarisation and Depolarisation. Hyperpolarisation  changes from -65mV to – 70mV. Depolarisation  changes from -65mV to -50mV.

Positive Potentials Small depolarisation with positive ions coming in, e.g. sodium. Bigger depolarisation as more positive ions come in, until you are at a positive membrane potential (i.e. crossed 0 point).

Conductance

Small depolarisation to a neuron. Following a small stimulation there is a small degree of depolarisation that decays along the length of the neuron  decremental conductance. Positive ions  positivity is bigger towards injection site, as opposed to away from injection site.

Action potential Increase the size of the stimulation and therefore the degree of depolarisation. When you cross a particular threshold, the neuron will fire - all or nothing threshold (around – 50mV).

Voltage Gated Channels Channels are ‘voltage-gated’ – opened when the membrane becomes depolarised. Different degrees of depolarisation open the channels. Look at properties using voltage clamp experiments. Positive membrane potentials (very high degrees of depolarisation) results in an inactivation of the Na+ channels. During action potential these channels play a critical role compared to resting/leaky channels.

Voltage Clamp Experiments - Sodium Inject a current into the axon to create a steady membrane potential. Can record the membrane current: product of what ions are moving across the membrane. At +52mV no current goes in any more, it all goes out.

Voltage Gated Channels - Sodium At rest voltage gated channels closed (-70mV). As current increases slowly, they start to open during depolarisation (-50mV). As current increases more, there is a refractory period, the channels temporarily shut down and sodium will not flow in.

After it has been activated, channel enters refractory period, and can’t be activated and no sodium can enter. Lower resting potential (-26mV to +26mV) sodium ion channels open. Higher resting potential (50mV to 65mV) sodium ion channels closed – refractory phase.

Voltage Gated Channels – Potassium At rest channels are mostly closed. As depolarisation begins, sodium voltage gated channels open, while potassium gated channels remain shut. At around -20mV to -10mV, potassium voltage gated channels open, potassium will flow out. No refractory period.

Action Potential – Sodium and Potassium Channels 1. At the resting membrane potential, the majority of the channels are closed. 2. Small depolarisation opens a few Na+ channels. Na+ begins to move into the neurone (diffusion and electrostatic forces) leading to further depolarisation. 3. If the stimulation is large enough (above the action potential threshold), the majority of the Na+ channels open and more Na+ moves into the neurone (diffusion and electrostatic forces), again leading to further depolarisation. 4. As the neurone continues to depolarise, some K+ channels are opened. Allowing K+ to leave the neurone (diffusion), but generally sodium is still dominating and hence depolarisation continues. 5. At positive potentials the Na+ channels become deactivated (refractory) so that no Na+ can pass through. The remaining K+ channels open, and K+ continues to leave

the neuron driven by both diffusion and electrostatic forces (as inside the neuron is now positive). 6. K+ continues to leave the neuron (diffusion). The membrane potential decreases and becomes negative  Repolarisation. 7. The K+ channels begin to close and Na+ channels return to their closed normal state. The membrane potential drops to below the resting membrane potential due to a few remaining open K+ channels, and the high concentration of K+ outside of the neurone  hyperpolarisation. During this time another action potential is difficult to elicit, as the cell is so negative. 8. The final K+ channels close and external K+ is diffused away. The membrane potential returns to the resting membrane potential. Na+/K+ pumps work hard to restore resting membrane potential.

Propagation of the Action Potential Along the Axon: Unmyelinated

The action potential is the same size at each point along the axon: all-or-none response.

Propagation of the action potential along the axon is unidirectional (unmyelinated).

Depolarisation spreads along the axon, this is how an action potential travels down the axon.

Sample Questions 1. Opening of the voltage-gated sodium channels is responsible for the repolarisation phase. (True/False). 2. In which part of the neuron do electrical impulses gather to generate an action potential? A) Axon hillock B) Axon terminal branch C) Dendrite D) Synaptic junction

Summary Resting membrane potential: -

Neurons have a negative resting potential due, primarily, to the selective permeability of the neuronal membrane to potassium ions. The long term imbalance of ions (potassium concentration: high inside; sodium concentration: high outside) is maintained by an active sodium – potassium exchange pump.

Action potential:

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When the membrane becomes excited (depolarised), voltage-gated ion channels are activated that lead to an action potential.

Myelination, Synapses, Receptors and Neurotransmitters (Neuronal Transmission II) Myelination

Myelin sheath  fatty tube placed around the axon by either oligodendrocyte or a Schwann cell.

Oligodendrocytes and Schwann Cells

Brain and spinal cord  oligodendrocytes. Sensory nerves  Schwann cells.

Propagation of the Action Potential Along the Axon Unmyelinated axon:

Myelinated axon:

In myelinated axons, the areas with no fatty coating (from either oligodendrocytes or Schwann cells), there are Nodes of Ranvier.

In myelinated axons, action potentials can only occur at the nodes of Ranvier as this is the only place where K+ and Na+ can pass through the channels. -

There is no ion exchange in the areas with fatty coverings.

Depolarisation decays along the length of myelinated sections. -

Depolarisation is built up at the Nodes of Ranvier, and then it decays through the myelinated sections. However, when the impulse arrives at the next Node of Ranvier, there needs to be enough depolarisation to trigger another action potential. This ‘jumping’ from one node to another speeds up the action potential.

Advantages of Myelinated Axon Generation of an action potential requires energy (e.g. sodium – potassium pump activation (ATP required)), and time. -

Less action potentials are needed to send a nerve impulse along a myelinated neurone than an unmyelinated neurone.

Multiple Sclerosis In multiple sclerosis the myelin sheath starts to degrade, to cause symptoms like loss of sensitivity, muscle weakness, difficulty with coordination and balance.

Toxins Tetrodotoxin (puffer fish)  blocks voltage gated Na+ channels – important for depolarisation, so no more nerve impulses  paralysis leading to respiratory failure. α -dendrotoxin (Green Mamba)  blocks voltage gated K+ channels – no repolarisation  convulsions voltage-Gated Na+ channel blockers used as anaesthetics: -

Lidocaine Benzocaine Cocaine – used in ear, nose and throat surgery.

The Synapse

Types of synapse: 1. -

Electrical synapse: Rare in adult mammalian neurons. Junction between the neurons is very small (3nm). Gap is spanned by proteins (connexins) which are used to communicate between the neurons (ions move freely).

2. -

Chemical synapses: Common in adult mammalian neurons. Junction between the neurons 20-50nm (synaptic cleft). Chemicals (neurotransmitters) are released from the presynaptic neuron to communicate with the postsynaptic neurons.

Chemical Synapses Vesicles with neurotransmitters. Dendritic spine – area receiving neurotransmitters. Bottom – postsynaptic neuron.

Synapse Location Most common synapse is axodendritic  axon impinges on dendrite. Axosomatic  axon to soma (inhibitory synapses usually). Axoaxonic  axon to another axon (sometimes inhibitory connections).

Why Does Synapse Location Matter?

Axodendritic synapse: Activation of an excitatory synapse leads to local and small depolarisation of the postsynaptic cell known as an EPSP (excitatory postsynaptic potential). EPSP decays over the length of the dendrite.

Therefore the closer the synapse is to the soma, the greater its influence on the production of an action potential in the axon. All inputs are summated at the some (cell body). If there is enough excitation then an action potential is generated at the axon hillock.

Properties of Chemical Synapses -

Neurotransmitters that have to be released. Postsynaptic receptors that receive the signals. Neurotransmitters are deactivated. Types of neurotransmitters.

Overview of Processes at the Chemical Synapses 1. Action potential travels down the axon. 2. When it gets to the synapse, depolarisation opens voltage-dependent calcium channels. 3. Influx of calcium leads to neurotransmitter release. 4. Neurotransmitter binds to and activates receptors on the dendrites of the postsynaptic cell. 5. This leads to depolarisation or hyperpolarisation of the postsynaptic cells. 6. This spreads to the postsynaptic soma, where summation occurs. 7. If there is enough depolarisation, then an action potential is generated at the axon hillock.

Neurotransmitters

Chemical that is used to transmit information from the presynaptic neuron to the postsynaptic neuron. Criteria for neurotransmitter: 1. 2. 3. 4.

Chemical synthesized presynaptically. Electrical stimulation leads to the release of the chemical. Chemical produces physiological effect. Terminate activity.

Dales Law  if a particular neurotransmitter is released by one of a neuron’s synaptic endings, the same chemical is released at all synaptic ending of that neuron. (But the dendritic field can receive signals from multiple transmitters).

Neurotransmitter Action

Neurotransmitter Release 1. Synaptic vesicle containing neurotransmitter ‘docked’ at the synaptic membrane. 2. Depolarisation of the presynaptic neurone leads to the opening of calcium channels and calcium influx (conc. Gradient). 3. Vesicles fuse with the synaptic membrane and releases neurotransmitter into the synapse. 4. Vesicle detaches from the docking zone.

SNARE proteins are what ‘dock’ the synaptic vesicle to the membrane.

Postsynaptic Action of the Neurotransmitter Neurotransmitter binds to receptors on the postsynaptic membrane, which affects the activity of the postsynaptic cell. The configuration of the receptors make them specific for different neurotransmitters.

Opening of an ionic channel (typically). Ionotropic receptor.

Activates an internal 2nd messenger systems that goes on to affect the functioning of the postsynaptic cells. Metabotropic receptor.

Ionotropic Receptor Protein subunits around a central pore. Neurotransmitter can bind, open up the ionotropic receptor, and ions can flow in. Fast transmission – ion movement leads to an immediate change in the postsynaptic cell.

Excitatory fast transmission: -

Ion channel opens. Movement of positive ions into the neurone (Na+) e.g. Glutamate receptors. Depolarisation. Excitatory post synaptic potential (EPSP).

Inhibitory fast transmission: -

Ion channel opens. Movement of negative ions into the neurone (Cl-) e.g. GABAa receptors. Hyperpolarisation. Inhibitory post synaptic potential (IPSP).

Metabotropic Receptor (G-Protein Coupled Receptors) Neurotransmitter binds to serpentine receptor, which is attached to a Gprotein.

Activation of a G-protein coupled receptor: 1. Neurotransmitter binds to receptor and activates the G-protein (exchange GDP for GTP). 2. G protein splits and activates other enzymes. 3. The breakdown of GTP turns off G protein activity. 4. Series of chemical reactions that leads to an amplification of the signal – second messenger system. Amplification Slow, however the effects are a lot bigger.

Example of amplification of signal through G-protein coupled receptor activation:

Neurotransmitter Deactivation Neurotransmitters must be inactivated after use to remove them from the synaptic cleft. -

Reuptake – like a vacuum that removes the neurotransmitters left in the synaptic cleft. Deactivating enzymes – break down the transmitters when they are in excess.

Classes of Neurotransmitters

Glutamate – excitatory. GABA – inhibitory.

Glutamate Major fast excitatory neurotransmitter in the CNS. Very widespread throughout the CNS. Activates different types of receptors: mGluR, NMDA, AMPA, Kainate.

Normal neuronal transmission (AMPA): Presynaptic release of glutamate

Postsynaptic activation of AMPA receptors

Influx of Na+

Depolarisation (EPSP) -

Involved in learning and memory processes.

Neural Integration: Boosting EPSPs Spatial integration  Three inputs at once, which creates one big EPSP. Temporal integration  Multiple action potentials coming from same axon, get a bigger response over a longer time.

GABA GABA – gamma aminobutyric acid. Major inhibitory transmitter. Activates an ionotropic receptor (GABAa receptor) which opens a chloride channel (Cl-) leading to hyperpolarisation (IPSP). GABAa Receptor Many drugs/hormones enhance its function: -

Ethanol (alcohol) Neurosteroids Benzodiazepine Barbiturate

Involved in anxiety. GABAs function is to slow you down (chill out).

Neural Integration: Interaction of Excitatory and Inhibitory Inputs EPSP decays over the length of the dendrite. Synapses close to the soma have a greater influence as there is less opportunity for the signal to decay. EPSP can be decreased or abolished by IPSPs from inhibitory neurons that are active at the same time or can be enhanced by EPSPs from excitatory neurons that are active at the same time.

Autoreceptors Located on presynaptic terminal. Respond to neurotransmitter in the synaptic cleft. Generally they are G-protein coupled: -

Don’t open ion channels Don’t cause depolarisation

Regulate internal process controlling the synthesis and release of neurotransmitter. Negative feedback mechanism – too much neurotransmitter in synaptic cleft, and so autoreceptor responds.

Sample Questions 1. 2. a) b) c) d) e)

GPCRs function much faster than ionotropic receptors (True/False). Activated GABAa receptors inhibit neurons by allowing: Potassium flux out of the cell. Chloride flux out of the cell. Chloride flux into the cell. Sodium flux out of the cell....