1. 8 Memory Formation: Post-Translation Processes

2. The goal of this chapter and several that follow is to determine if some of the processes that have been identified in establishing LTP are involved in making behavioral memories. We are going to focus on three major players: Glutamate Receptors (NMDA and AMPA) CaMKII Memory Formation: Post-Translation Processes

3. The NMDA receptor is critical to many forms of LTP. Is the NMDA receptor the gateway to the acquisition of a behavioral memory? This was the question Richard Morris addressed in his classic 1986 paper. This paper was a classic because it was the first to outline an approach to the problem and produce some reasonable data. NMDA Receptors and Memory Function

4. NMDA Receptors and Memory Function: Figure 8.2 The NMDA receptor and place learning (Part 1)

5. NMDA Receptors and Memory Function: Figure 8.2 The NMDA receptor and place learning (Part 2)

6. NMDA receptors are composed of NR1 and NR2 subunits. All functional receptors contain NR1 subunits. NR1 subunits come in two categories, NR2A and NR2B. NMDA Receptors and Memory Function: Figure 8.3 Genetically modifying the composition of the NMDA

7. NMDA Receptors and Memory Function: Figure 8.4 Deletion of the NR1 subunit in CA1 (Part 1)

8. NMDA Receptors and Memory Function: Figure 8.4 Deletion of the NR1 subunit in CA1 (Part 2)

9. NMDA Receptors and Memory Function: Figure 8.4 Deletion of the NR1 subunit in CA1 (Part 3)

10. NMDA Receptors and Memory Function: Figure 8.5 Enhancing the NR2B subunit contribution This figure illustrates the shift in the ration of NR1–NR2A and NR1– NR2B NMDA receptors that takes place as the brain develops. Top: During the early postnatal period there are relatively more NR1– NR2B receptor complexes. Bottom: With maturation there is a shift in the balance so that there are now more NR1–NR2A receptor complexes.

11. NMDA Receptors and Memory Function: Figure 8.6 Enhancing the NR2B subunit contribution

12. Song birds express increased mRNA for the NR2B subunit during the season when they are learning their mating song. NMDA Receptors and Memory Function: Figure 8.7 Natural variation in NR2B subunits

13. NMDA Receptors and Memory Function: Some Caveats There is no doubt that NMDA receptors can make a critical contribution to memory formation. However, it is also important to note that there are many reports that memories can be formed even in the face of a strong blockade of NMDA receptors.

14. Results Rats first trained on the task in Room 1. Phase 1Phase 2 Rats trained on the task in Room 2 were injected with APV. LTP in DG was blocked but APV had no effect on place learning. Thus pretraining in a different room abolished the behavioral effects of antagonizing NMDA receptors. NMDA Receptors and Memory Function: Some Caveats

15. Drugs and genetic manipulations can modify behavior without affecting learning and memory processes. These agents can have multiple effect. Even if the targeted molecule or receptor does make a contribution to memory, it might be involved in some other component system that influences behavior. Memory formation may take place without the contribution of NMDA receptors. This means that there are other mechanisms that can produce memories when NMDA receptors are not functional. However, this does not exclude the possibility that NMDA receptors normally contribute to creating memories. NMDA Receptors and Memory Function: Some Caveats

16. General Point When a component of the brain is removed and this has no effect on memory formation, one cannot say the component (e.g., brain region, cell, or molecule) is not involved in memory formation when it is normally present. The brain has redundant mechanisms that might substitute for each other. So, the absence of an effect primarily tells us what the brain can do without the component. It does not tell us what that brain component does in the normal brain. NMDA Receptors and Memory Function: Some Caveats

17. AMPA Receptors and Memory Function: Figure 8.8 AMPA receptors and memory formation

18. AMPA Receptors and Memory Function: Figure 8.9 AMPA receptors and memory formation

19. AMPA Receptors and Memory Function: Figure 8.10 Ampakines enhance AMPA receptor function

20. Based on what you have learned about the role of NMDA receptors in synaptic plasticity in the hippocampus, you might expect that they contribute to acquisition but not the retrieval of memory. You might also expect that AMPA receptors contribute to both the acquisition and retrieval of the memory. Figure 8.11 NMDA and AMPA receptors make different contributions to acquisition and retrieval

21. CaMKII and Memory Formation: Figure 8.12 CaMKII knockout mice show impaired place learning

22. CaMKII and Memory Formation: Figure 8.13 Autophosphorylation is critical for rapid formation of a fear memory

23. CaMKII and Memory Formation: Figure 8.14 Fear conditioning phosphorylates CaMKII