1. D ISTINCT C OMPONENTS OF S PATIAL L EARNING R EVEALED BY P RIOR T RAINING AND NMDA R ECEPTOR B LOCKADE Group B3 Abdullah, Barbara, Charles, Charmaine, Margaret and Sarah

2. O UTLINE 1. Summary of the results 2. Confounding Variable: AP5 Administration 3. Controlling AP5 Administration 4. Supporting Evidence 5. Application to Human Studies Sarah

3. S UMMARY OF F INDINGS Exp.MethodsResults 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

4. S UMMARY OF F INDINGS Exp.MethodsResults 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

5. O VERALL C ONCLUSIONS 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

6. A MOUNT OF AP5 A DMINISTRATION 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

7. C ONTROLLING FOR D RUG D OSAGE : 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

8. S UPPORTING E VIDENCE 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

9. C ONCLUSIONS 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

11. 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

12. A PPLICATION TO H UMAN S TUDIES 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

13. Any Questions or Comments?