Distinct Components of Spatial Learning Revealed by Prior Training and NMDA Receptor Blockade

1. Distinct Components of Spatial Learning Revealed by Prior Training and NMDA Receptor Blockade Group B3 Abdullah, Barbara, Charles, Charmaine, Margaret and Sarah

2. Sarah Outline • Summary of the results • Confounding Variable: AP5 Administration • Controlling AP5 Administration • Supporting Evidence • Application to Human Studies

3. Barbara Summary of Findings

4. Barbara Summary of Findings

5. 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

6. 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

7. 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)

8. Charmaine 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

9. Conclusions Charmaine 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

10. Charmaine

11. 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?

12. Sarah 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.

13. Any Questions or Comments?