Lecture 21; Synapse Plasticity 3

Question 1

What is a common theme of neurodegenerative disorders?

Answer 1

All disorders directly or indirectly affect synapse function

Question 2

What do clinical symptoms result from?

Answer 2

Altered Sub-cellular function

Question 3

What is the value of mouse models?

Answer 3

•Mouse models of neurological disorders provide the opportunity to define abnormal cellular mechanisms

Question 4

What is the best animal model for human down syndrome?

Answer 4

Ts65Dn

Behavioural studies show these animals reflect humans

Question 5

What is down syndrome characterised by?

Answer 5

DS is characterized by impairments in learning and memory. Abnormalities in explicit memory point to involvement of the hippocampus

Question 6

What trisomy does the Ts65Dn have?

Answer 6

The Ts65Dn mouse is segmentally trisomic for mouse chromosome 16 and carries three copies of genes orthologous to those on human chromosome 21

Question 7

What behaviours do the Ts65Dn mice display?

Answer 7

Ts65Dn mice exhibit features characteristic of DS, including impairment of learning and memory

Question 8

What does the Ts65Dn mouse not do that is severely abnormal?

Answer 8

LTP can be induced within the dentate gyrus with tetanic stimulation in normal mice but not in Ts65Dn mice

Question 9

What causes the lack of LTP in Ts65Dn mice?

Answer 9

•NMDA receptor mediated currents are reduced in Ts65Dn mice•This likely underlies their reduced ability to undergo LTP

Question 10

Instead of LTP what does the Ts65Dn mouse have?

Answer 10

•Ts65Dn mice display a higher frequency of inhibitory currents

Question 11

How was it determined that these mice have higher Hz of inhibitory currents?

Answer 11

Pharmacologically

Increased inhibition = decreased RMP

Therefore low NMDA currents as not enough stimulation to remove the Mg from the pore

Question 12

What happened when the inhibition was reduced pharmacologically?

Answer 12

• Once inhibition was reduced pharmacologically, NMDA responses returned to normal size.
• The ability to induce LTP was also restored

Question 13

What drug was used to block the inhibitory current?

Answer 13

Picrotoxin

Must be careful to balance excitation and inhibition to prevent seizures

Question 14

Describe how Treatment of overinhibition improves cognition in Ts65Dn mice was measured.

Answer 14

•Treated for 4 weeks with non-epileptic doses of picrotoxin•Novel recognition task was performed to assess cognitive function

Question 15

What was the conclusion of the picrotoxin study?

Answer 15

Examined synaptic plasticity in animals that had been treated for 3-4 weeks•Drug treatment resulted in the rescue of LTP•Effect lasted for up to 3 months after drug treatment

Picrotoxin rescues LTP within the hippocampus

Question 16

Does altered synaptic function underly the cognitive deficits in DS?

Answer 16

• Downs Syndrome mice display impairments in NMDA receptor activation as a result of increased inhibition. (decreased NMDA current and LTP)
• This results in a decreased ability to undergo LTP and decreased cognitive function.
• Treatment to prevent increased inhibition leads to rescued LTP and improved performance on cognitive tasks in Downs Syndrome.

•These findings suggest that similar changes contribute to abnormalities in learning and memory in people with DS.

Question 17

What is huntingtons disease?

Answer 17

•Individuals carrying the mutation for HD have such an expanded glutamine repeat in huntingtin, a 350 kDa protein of unknown function.

Neurodegenerative Disorder
Multifunctional
Transcription factor
Cell wiring
Transport protein

Question 18

What is the characteristics of HD?

Answer 18

•Cognitive defects, including memory and information-processing deficits, mood changes, aggressive behavior and disruptions in spacial memory, occur before the movement impairments associated with later stages of the disease

Question 19

What mouse was created to model HD?

Answer 19

Mice were engineered to carry the HD mutation in the endogenous huntingtin gene (YAC128 mice).

Question 20

Are PSD receptors immobile?

Answer 20

As well as being anchored in the PSD, receptors move between synaptic sites (in the PSD) and extrasynaptic sites (outside the PSD)

Question 21

What is the function of receptors in the synapse?

Answer 21

Activation of synaptic receptors activates maintenance pathways

Question 22

What are the function of receptors outside of the synapse?

Answer 22

Activation of extrasynaptic receptors activates cell death pathways

Question 23

What is special about Extra synapse receptors?

Answer 23

They can diffuse freely

Some evidence that LTP extra synaptic receptors can diffuse into the synapse

Question 24

What happens to receptors in HDs?

Answer 24

Number of extra synaptic receptors increases.

Therefore these once activated can lead to activated cell death pathways (apoptosis)

There is also increased glutamate in synpases in HD so increased risk

Question 25

What is the use of TBOA and what did it show in YAC128 mutants?

Answer 25

• TBOA is a drug that increases the amount of glutamate at the synapse, and therefore activates both synaptic and extrasynaptic receptors
• YAC128 mutant mice show much higher amounts of current through NMDA receptors at extrasynaptic sites

Question 26

What does blocking these extra synaptic receptors in HD mice do?

Answer 26

Blocking extrasynaptic receptors rescues motor learning in HD mutant mice

(memantine blocks the extra synaptic NMDA receptors as they have a slightly different sub unit)

Question 27

How can synapse function be altered?

Answer 27

•Synapse function can be altered in many ways
–Changes in excitation-inhibitory balance
–Changes in receptor localisation
–Changes in transmitter release, receptor function, receptor number….