Dean NMR 6

Question 1

What is the debate about drugs in this area?

Answer 1

Drugs enhancing memory would accumulate interest in regard to clinical conditions such as Alzheimer’s and also for everyday life e.g. exams
But should there be such a drug?

Question 2

What about drugs for the cerebellum?

Answer 2

They could perhaps help with motor skills

Question 3

What are the assumptions about conditioning in the cerebellum so far?

Answer 3

1. During conditioning, the CS is paired with the US so that parallel fibre firing is paired with firing in the climbing fibres
2. Theory predicts that the PF-PC synapses become less effective by a process termed LTD
3. Assumed that the inhibitory pathway is unchanged
4. Therefore, PCs receive a net inhibitory input when the CS comes on after conditioning
5. The PCs pause thereby releasing firing in the AIPN

Question 4

What did Medina and Mauk (2000) do?

Answer 4

They produced a computer simulation of cerebellar information processing

Question 5

Is there evidence for LTD in the cerebellum?

Answer 5

Yes (Ito, 1984; 2002)
There is a huge amount of evidence
Mainly found in slices in vitro (in glass) which are very thin slices of neural tissue kept in a small dish of liquid and can be looked at using a microscope

Question 6

Why is it good to use slices?

Answer 6

Using a hydraulic steel table for slices removes vibrations from foot steps, traffic etc. so you can keep recording from the cell for long periods - important for studying plasticity effects
Can control for artefacts
Any movement from the animal itself e.g. blood flow is eliminated
Can see what cell the electrode is recording from and control the chemical environment in the cell e.g. can block the plasticity

Question 7

What are the typical results found from the slices?

Answer 7

Once stimulation of parallel fibres and climbing fibres is paired, and the stimulation of climbing fibres is stopped
Can see that the purkinje cell response has been reduced

Question 8

What does LTD do?

Answer 8

Makes EPSPs smaller

Question 9

What happens at the parallel fibre - purkinje cell synapse?

Answer 9

It uses glutamate as a neurotransmitter
Has 2 kinds of post synaptic receptor
1. ionotropic glutamate receptor
2. metabotropic glutamate receptor

Question 10

Outline the ionotropic glutamate receptor

Answer 10

The familiar, conventional kind which was originally described 50-60 years ago
When it is activated by glutamate it opens to allow ions to flow into the cell - hence the name ionotropic
Give rise to EPSPs and APs if strong enough

Question 11

What are ionotropic glutamate receptors called on purkinje cells?

Answer 11

AMPA receptors

Question 12

Outline the metabotropic glutamate receptor

Answer 12

The less familiar kind which was discovered around 30 years ago
When activated by glutamate they act on signalling machinery inside the cell which alters the cell metabolism

Question 13

What is an example of a metabotropic glutamate receptor in purkinje cells?

Answer 13

mGluR1 (metabotropic glutamate receptor type 1)

Question 14

What is the possible mechanism of LTD?

Answer 14

1. Parallel fibres firing activates both the AMPA and mGluR1 receptors
2. mGluR1 activations start a cascade of processes in the cell
3. If the climbing fibre also fires, this cascade continues until some AMPA receptors are removed
4. Removal of AMPA receptors reduces amplitudes of EPSPs induced by parallel fibre stimulation e.g. LTD

cells are extremely complex factories

Question 15

What is the first problem with slices?

Answer 15

Slices are ‘unnatural’ - they have no afferents, no blood supply.
So we cannot assume that the processes observed in slices are necessarily present in the intact brain

Question 16

What is the second problem with slices?

Answer 16

Even if the LTD observed in the slices was present in the intact brain, it might not necessarily be there for learning
It might have a protective, homeostatic function

Question 17

What can implications from slice studies be used for?

Answer 17

Results from slices can lead to hypotheses about functions in the whole animal
Need experiments that can link the biochemistry and behaviour in order to test said hypotheses

Question 18

What is one technique for testing the hypothesis that removing AMPA receptors mediates eye blink conditioning?

Answer 18

Breed mutant mice that specifically lack the necessary cellular machinery to remove AMPA receptors - ‘knockout mice’
These mice lack LTD in slices but show normal eye blink conditioning
This is UNEXPECTED, raises questions

Question 19

What is one possibility for this knockout mice finding?

Answer 19

That it involves a new form of plasticity recently suggested by the Lund group

Question 20

What did the Lund group do?

Answer 20

Looked at a decerebrate ferret and recorded from Purkinje cells
Found that training produces a pause in simple spike firing but this is still present even if the mGluR1 receptor is blocked - this is consistent with K/O mice
However, this pause disappears if the mGluR7 receptors are blocked

Question 21

Why was the Lund group’s findings unexpected?

Answer 21

As the AMPA receptors were not involved at all
Not much is known about mGluR7 receptors but they appear to act on a protein that activates a potassium channel
This activation inhibits the Purkinje cell
Could work in principle but finding is recent so hasn’t got replications which are important as intact animals need to be used

Question 22

What is a second possibility from the unexpected K/O finding?

Answer 22

That the procedure just needed to be changed
Schoneville et al. found that LTD could be obtained in mutants if the induction procedure was changed
Raises issue with in vitro results and also raises question of what the underlying mechanism of this form of LTD is if it isn’t the removal of AMPA receptors

Question 23

What is the current stance on the sites of plasticity in NMR conditioning?

Answer 23

Even for a simple task such as eye blink conditioning we do not understand the mechanisms of synaptic plasticity
So clearly we need to learn more before offering candidate drugs for memory enhancement