Lecture 5 - Cells of the nervous system 2

Question 1

What is glutamate?

Answer 1

Glutamate is toxic to nerve cells and can cause nerve cell death

Question 2

What is neurotransmitter handling?

Answer 2

• Neurotransmitters are molecules released into extracellular space by a neurone that elicit a response in other neurones
• To have full control over the responses produced by a neurotransmitter it is necessary to:
◦ control its release
◦ ensure it does not reach high extracellular concentrations
◦ prevent it diffusing to other neurones where it is not required

Question 3

What is extracellular space?

Answer 3

• In between nerve cells and supporting cells is extracellular space
  
  • Molecules don’t leave one cell and head to the next, molecules move anywhere, they reach receptors by chance using diffusion.

Question 4

How has neurotransmitter handling evolved?

Answer 4

• to prevent continuous stimulation of post-synaptic cells
  
  • to alter (shape) the post-synaptic response
  • to regulate pre-synaptic release
  • to prevent excitotoxicity
  • to control the effects on nearby neurones

Question 5

What types of proteins are involved in neurotransmitter handling?

Answer 5

• Post-synaptic receptors
  
  • Pre-synaptic receptors
  • Uptake or degradation mechanisms
  • Transporters
  • Synthetic enzymes - making the neurotransmitter

Question 6

What happens at the synapse? (1)

Answer 6

• An action potential arrives in the pre-synaptic terminal
  
  • It causes vesicles to fuse with the pre-synaptic membrane
  • The contents of the vesicle (neurotransmitter) are released into the synaptic cleft

Question 7

What amino acid neurotransmitters are there?

Answer 7

• GABA - an inhibitory molecule
  
  • Glutamate - fats excitatory synapses - when rapid response is needed, travels rapidly across the path way. Used in ear?
  • Glycine

Question 8

What amine neurotransmitters are there?

Answer 8

• Dopamine
  
  • Acetylcholine - an excitatory molecule
  • Epinephrine
  • Histamine
  • Norepinephrine
  • Serotonin

Question 9

What peptide neurotransmitters are there?

Answer 9

• Enkephalins (pain control, endorphins)
  
  • Somatostatin (inhibitory hormone with neural effects on growth, gastrointestinal system)
  • Substance P (pain signalling)

Question 10

How does the synthesis of Glutamate occur? •

Answer 10

• Glutamate – a common amino acid metabolite, not specific to nerve cells, synthesised in many ways. In nerve cell synthesises around the mitochondria.

Question 11

What is synaptic transmission?

Answer 11

• At the end of the synapse, there are synaptic vesicles
  
  • These synaptic vesicles, contain neurotransmitters
  • When an action potential reaches the end of the synapse, these vesicles release their neurotransmitters
  • These fuse and carry signals across the synaptic gap

Question 12

What do transporters do?

Answer 12

• Removal of amino acids and some amines from the synapse
  
  • Glutamate transporters occur in glial and nerve terminal membranes
  • Dopamine and serotonin transporters occur in nerve terminal membranes
  • The location of these varies

Question 13

What is the glutamate-glutamine cycle

Answer 13

• Glutamate is removed from the synaptic cleft by the excitatory amino acid transporters(EAATS)
  
  • The EAATS carry glutamate into neurons and glial cells
  • Glutamate in glial cells is converted into glutamine by glutamine synthetase
  • Glutamine is then transported back into neurons where it is then converted to glutamate

Question 14

How does a glutamate transporter work?

Answer 14

• After the cell releases glutamate into the synapse
  
  • Glutamate transport pumps the glutamate back into the neuron or neighbouring glial cells
  • This protein is the key to regulating glutamate, too much is toxic and the main cause of many neurodegenerative diseases

Question 15

What are the physiological actions of transporters?

Answer 15

• Transporters can affect the way that the synapse works

Question 16

What are other forms of neurotransmitter deactivation?

Answer 16

Reuptake by endocytosis
Acetylcholine is deactivated by acetylcholinesterase released by muscles at the neuromuscular junction
Some neurotransmitters are deactivated by enzymes released into the synaptic cleft

Question 17

What is the first thing occurring during neurotransmitter handling in a post-synaptic cell?

Answer 17

Neurotransmitter activates postsynaptic receptors of which there are two main types:
◦ Ionotropic: results in ion entry to modify receptor potential
◦ Metabotropic: results in a second messenger system within the postsynaptic (and/or sometimes presynaptic) neurone
Neurotransmitter does not enter the post-synaptic cell through the receptors

Question 18

What is Excitotoxicity?

Answer 18

• Overstimulation of nerve cells
  
  • Leads to nerve cell damage and death
  • Can cause brain damage that cant be repaired
  • Prominent in research
  • Happens within a few minutes of oxygen deprivation

Question 19

Who first observed Excitotoxicity, and how was it discovered?

Answer 19

Hayashi in 1954

Direct application of glutamate to the CNS caused seizure activity

Question 20

What happens if there is excess glutamate at the synapse?

Answer 20

• If uptake fails, the post-synaptic neuron can die either rapidly via necrosis (rapid death?), or slowly via apoptosis (controlled death)

Question 21

What mechanism affects the release of glutamate?

Answer 21

• One proposed mechanism is that ischemia affects the release of glutamate

Question 22

What mechanism can affect the inability to extract glutamate from the extracellular space?

Answer 22

• Inadequate ATP production resulting from brain trauma can eliminate electrochemical gradients of important ions
  
  • Glutamate transporters require the maintenance of normal ion gradients in order to remove glutamate from the extracellular space

Question 23

How can ion gradients reverse the glutamate transporter?

Answer 23

• Glutamate uptake is highly dependent on ion gradient
  
  • Collapse of a sodium gradient will stop glutamate uptake and in some cases will cause a transporter to operate in reverse direction releasing glutamate into the synaptic space

Question 24

What did Werth discover?

Answer 24

• Werth showed that, upon oxygen and glucose deprivation of less than ten minutes, neuronal swelling, degeneration and death occur in tissue slices.

Question 25

How can some areas of the brain be more susceptible to excitotoxicity?

Answer 25

• Hippocampal neurones are particularly rich in NMDA receptors and are more vulnerable to elevated glutamate under conditions of global hypoxia or anoxia
  
  • Glutamatergic pathways in the hippocampus are widespread
  • Damage varies from structure to structure depending on the extent of glutamatergic innervation

Question 26

What diseases can excitotoxicity correlate with?

Answer 26

• Defective glutamate uptake has been suggested to be important in connection with:
  
  • amyotrophic lateral sclerosis
  • Alzheimer’s disease
  • Epilepsy
  • Intoxication
  • AIDS
  • Traumatic brain injury

Question 27

What is diffusion?

Answer 27

• Diffusion means that neurotransmitter does not stay in the synaptic cleft but diffuses away from the synapse in between the cells.
  
  • Diffusion is high concentration to low concentration

Question 28

Why is diffusion a problem

Answer 28

• Diffusion is a problem because can affect other targets
  
  • The main effect is on the post-synaptic neurone (excitation, inhibition, potentiation)
  • However, they can sometimes affect the pre-synaptic cell and other nearby neurones (cross-talk)

Question 29

What happens at the synapse? (2)

Answer 29

Neurotransmitter in the cleft activates receptors

At the same time the neurotransmitter is being deactivated and/or recycled

Question 30

What happens at the synapse? (3)

Answer 30

Uptake or degradation of the neurotransmitter helps terminate the action
Sometimes, pre-synaptic receptors are present and when activated, affect the release (feedback)
Receptors on other neurones may be activated

Question 31

How does synthesis of Amines occur?

Answer 31

GABA and amines – synthesized within the terminal cytosol and taken up into vesicles

Question 32

How does the synthesis of Peptides occur?

Answer 32

Peptides – synthesized in the ER and Golgi apparatus and packaged into secretory granules

Question 33

What are the disadvantage of transporters?

Answer 33

• If they stop removing the neurotransmitter, synaptic activity can change
◦ desensitisation of post-synaptic receptors can occur
◦ long term depression of synaptic activity can be altered (glutamate)
◦ failure of uptake can cause excitotoxicity (glutamate)

Question 34

Who else also observed the excitotoxicity and how?

Answer 34

The toxicity of glutamate was also observed by Lucas and Newhouse in 1957
They fed monosodium glutamate to newborn mice which destroyed the neurons in the inner layers of the retina

Question 35

Who is John Olney?

Answer 35

discovered that the phenomenon occurred throughout the brain and called it excitotoxicity (1969)

Question 36

What happens in normal conditions with glutamate at the synapse?

Answer 36

• During normal conditions, glutamate concentration can increase up to 1mM in the synaptic cleft

Question 37

What happens at the pre synaptic membrane within the ischaemic mechanism?

Answer 37

• Pre-synaptic calcium increases due to failure of homeostatic mechanisms, ATP is decreased and excess glutamate is released

Question 38

What happens at the post synaptic membrane within the ischaemic mechanism?

Answer 38

• Post-synaptic glutamate (NMDA) receptors are overstimulated and allow an increased influx of calcium into the post-synaptic membrane

Question 39

How does loss of ion gradients affect the inability to extract glutamate from the extracellular space?

Answer 39

• Loss of ion gradients results not only in failure of glutamate uptake, but also in the reversal of the transporters

Question 40

What happens in response to the failure of ‘reversal of transporters’?

Answer 40

• This causes them to release glutamate and aspartate into the extracellular space
  
  • There is a buildup of glutamate and further activation of glutamate receptors

Question 41

How is swelling and degeneration found by Werth are reduced?

Answer 41

• Swelling and degeneration in tissue slices are reduced by administering MK-801, a chemical analog of glutamate
  
  • MK801 blocks the glutamate-gated ionotrophic receptor
  • MK801 decreases calcium and sodium entry and prevents the neurotoxic cascade