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 D. M. Bannerman, M.A. Good, S.P. Butcher, M. Ramsay & R. G. M. Morris Group B6 Margarita Blajeva Caitlin H. Cheong Pari Chowdhary Wissam A. Samad Brooke Thornton

2. Pari Long-Term Potentiation • Long-lived ↑ in synaptic strength • LTP and memory • associativity • N – methyl – D – aspartate (NMDA) receptor

3. Pari NMDA Receptor • NMDAR • Voltage – dependent glutamate receptor • Activated in LTP Adapted from http://web.sfn.org/index.cfm?pagename=brainBriefings_schizophreniaAndCognition&print=on

4. Pari AP5 • D(-)-2-amino-5-phophonovaleric acid • NMDA –receptor antagonist • Intracerebroventricular (ICV) administration • Impairs water maze acquisition • Blocks LTP induction

5. Pari Research Issue What component of spatial learning do blocked NMDA receptors affect? Can this effect be prevented?

6. Pari Experimental Apparatus P Adapted from http://btc.bol.ucla.edu/mwm.htm

7. Pari Hypothesis Does an AP5-induced inhibition of NMDA receptor functioning ALWAYS produce a learning deficit in spatial learning?

8. Brooke Experiment1 Purpose: To determine how AP5 affects rat performance in a water maze task

9. Brooke Methodology • Habituation and training ‘upstairs’ • ½ AP5 rats and ½ aCSF rats • Trained in a water maze to find platform

10. Escape latency decreases in aCSF rats over trials Brooke FIGURE 1 a

11. aCSF rats learnt and spent more time, over trials, in the quadrant with the platform Brooke FIGURE 1 b

12. Brooke LTP is normal in aCSF rats FIGURE 1 c

13. Brooke Results • The rats implanted with AP5 had no decrease in escape latency • The rats with aCSF were able to learn the task • LTP is blocked only in AP5 rats

14. Brooke

15. Margarita Experiment 2 Purpose: To dissociate the alternatives of spatial learning

16. Margarita Methodology • pretrained in a different ‘downstairs’ water maze • i.c.v. infusion of AP5 or aCSF • trained on the ‘upstairs’ spatial task

17. Margarita Hypothesis If NMDA receptors are necessary for forming a spatial representation of a new environment, an AP5-induced deficit in learning should still be present

18. aCSF and AP5 rats showed a decline in escape latency across trials Margarita FIGURE 2 a

19. Margarita FIGURE 2 b

20. Both groups showed a strong bias towards searching in the training quadrant Margarita FIGURE 2 c

21. Margarita FIGURE 2 d

22. Margarita LTP Blockade in vivo FIGURE 2 f

23. Pari Experiment3 Purpose: To see if spatial pretraining reduces the necessity for hippocampal involvement in spatial learning in a novel environment

24. Pari Methodology • Trained in the same spatial pretraining task downstairs • Given either: ibotenic acid lesions to hippocampus sham surgery left unoperated • Trained on exactly the same spatial learning task upstairs

25. A lesion-induced deficit in escape latency and transfer test performance was clearly apparent. Pari FIGURE 2 g

26. Pari Implications Spatial learning remains hippocampus-dependent after previous training in a similar task

27. Wissam Experiment 4 Purpose: To test whether non-spatial pretrainingis sufficient in eliminating the AP5 deficit in learning the water maze

28. Wissam Methods • Extraneous cues were obscured • Platform was placed/hidden in a different location on each trial • Pre-trained downstairs, then AP5 and aCSF pumps put in, and trained in upstairs maze.

29. Wissam FIGURE 3 a

30. Wissam FIGURE 3 b

31. Wissam FIGURE 3 c

32. Wissam FIGURE 3 d

33. Wissam Perforant Pathway Adapted from http://thebrain.mcgill.ca/flash/a/a_07/a_07_cl/a_07_cl_tra/a_07_cl_tra.html

34. Wissam FIGURE 3 e

35. Wissam Results • Longer escape latencies “downstairs” • AP5 deficit in learning “upstairs” task reappeared. • aCSF group focused search around training quadrant. • AP5 group  near-random searching in appropriate quadrant.

36. Wissam Summary

37. References Bannerman, D. M., Good, M. A., Butcher, S. P., Ramsay, M., & Morris, R. G. (1995). Distinct components of spatial learning revealed by prior training and NMDA receptor blockade. Nature, 378, 182-186. Martinez, J. L., & Derrick, B. E. (1996). Long-term potentiation and learning. Annual Review of Psychology, 47, 173-203.