DISTINCT COMPONENTS OF SPATIAL LEARNING

REVEALED BY PRIOR TRAINING AND NMDA RECEPTOR BLOCKADE

Group B3Abdullah, Barbara, Charles, Charmaine,

Margaret and Sarah

OUTLINE

1. Summary of the results 2. Confounding Variable: AP5

Administration 3. Controlling AP5 Administration4. Supporting Evidence 5. Application to Human Studies

Sarah

SUMMARY OF FINDINGS Exp. Methods Results

1

- Male Lister rats given AP5 or aCSF - Trained in watermaze to find a hidden escape platform

 -Rats given AP5 failed to learn: no decrease in escape latency but failed to search within the appropriate quadrant of the pool - AP5 also blocked rat’s capacity for LTP - Rats infused with sCSF learned task normally

2

- Rats pre-trained in another watermaze in separate lab (downstairs) - AP5 or aCSF infused

-Rats treated with AP5 learned well: showed steady decrease in escape latency- AP5 rats were slower than aCSF group- Still showed blockage of LTP- Spatial pre-training in a different location improved AP5 deficit seen in experiment 1 (despite block of LTP)

Barbara

SUMMARY OF FINDINGS Exp

.Methods Results

3

-Rats were trained in downstairs spatial pre-training task-then given: ibotenic acid lesions, sham surgery, or left un-operated on - Then, trained on exactly the same spatial learning task upstairs

- Lesion induced deficit was evident - Spatial learning is hippocampus-dependent after previous training in a similar task - Must be that disrupting NMDA receptors interferes with non-spatial procedural learning

4

- Rats pre-trained in environment that minimized the opportunity for spatial learning - Curtains were drawn around maze, platform hidden in different location every trial

- AP5 deficit in learning task upstairs reappeared - AP5 groups also showed near-complete blockage of LTP - Non-spatial pre-training fails to prevent the AP5 deficit of spatial learning

Barbara

OVERALL CONCLUSIONS

Results show significant triple interaction between drug group, pre-training and testing With NO pre-training, rats treated with AP5

cannot learn Non-spatial pre-training allowed some level of

learning Spatial pre-training mostly lifter AP5 induced

deficits

AP5 infusion leading to blockade of LTP disrupts both spatial and non-spatial components of water maze task

Barbara

AMOUNT OF AP5 ADMINISTRATION Experiment 4: Test effects of non-spatial pre-training

Results demonstrate that AP5 in non-spatial pre-training (& LTP blockage)= poor performance in maze reappeared

HOWEVER, amount of AP5 administered was not strictly controlled for

Consequence of lack of control: excess administration of AP5 would disrupt NOT ONLY spatial, but non-spatial components of Water Maze learning

Need another experiment to control for amount of AP5 administered!

Why control for this? Can directly measure if non-spatial pre-training (when spatial learning is disrupting) can account for normal performance in Morris Water Maze

Barbara

CONTROLLING FOR DRUG DOSAGE : Study: Testing the NMDA, LTP and Cholinergic Hypothesis of Spatial

Learning

Experiment: Pre-trained in non-spatial task Then injected with NMDA and Muscarninc Retested in Morris Water Maze

Findings: These antagonists did NOT affect rat’s ability to

apply instinctive behaviours (i.e. using the platform as refuge) in an adaptive manner

Plastic changes involved in a acquiring task occur in sensory, motor and other cortices (not places specifically implicated in spatial learning)

Barbara

SUPPORTING EVIDENCE

Aim/Methods:

To evaluate the ability of the conventional NMDA antagonist CGS19755 (CGS) to block LTP induced by long (125 ms) trains of high-intensity pulses, and the ability of non-spatially pre-trained rats to acquire the maze task when given the same dose of CGS.

Expt. 2 explored the role of NMDA receptors in visual discrimination learning relevant to the water maze task.

The role of NMDA receptors and NMDA-mediated hippocampal (LTP) in spatial learning was studied in rats using the competitive, systemically administered NMDA receptor antagonists CGS19755 and NPC17742

Charmaine

CONCLUSIONS

Rats given non-spatial pre-training in the general strategies required in the task, acquired it as

effectively as controls when trained under a dose of CGS that completely blocked LTP in the

dentate gyrus of the same rats

Charmaine

Charmaine

Question:

It is not known why hippocampal damage impaired

performance of the water maze task even though the rats were capable of acquiring spatial information or learning a place response?

Charmaine

APPLICATION TO HUMAN STUDIES

Experiment: Attempted to determine whether neocortical LTP

was deficient in Alzheimer’s Disease (AD) patients as well as in APP/PS1 mice – an AD animal model.

Then examined LTP deficit in relation to NMDA receptor abnormalities.

Compared AD patients with matched controls on a paired associative stimulation task

  Analyzed neocortical and hippocampal brain slices of APP/PS1 mice

Results: AD patients and mice both showed a deficit in

NMDA-dependent forms of LTP. Biochemical analysis showed impaired NMDA function in mice.

Sarah

Any Questions or Comments?