Lecture 6 - LTP and learning, Genes

Lecture 6 - LTP and learning, Genes

1. So, is NMDA receptor-dependent LTP not necessary for spatial learning? Or are we just not using the best tools for the question?

   • Maybe the drugs don’t work, they have side effects. AP5 effects on NMDAR outside the hippocampus: cause ataxia; change in motivation state (less anxious); cause weight loss

2. Genetic manipulation

   • Genetic manipulations potentially avoid the problems with pharmacological manipulation. The function of the NMDA receptor can be directly manipulated by deleting the gene responsible for particular receptor subunits. Genetic manipulations can be targeted to particular brain areas with greater accuracy than drug manipulations

3. Tang et al, 1999. Doogie mice – NR2B over expression

   • Here is a different way of tackling the question of whether LTP = learning. Hypothesis: Enhancing LTP will enhance learning. LTP can be enhanced by increasing the expression of the NR2B subunit of the NMDA receptor
     • Doogie mice showed superior spatial learning in the Morris water maze than controls Doogie mice also showed enhanced object recognition memory.

4. So, if overexpressing NR2B enhances learning, then what does knockout of NR2B do?

   • NR2B knockout mice are impaired on lots of behavioural tasks that assess learning. Consequently, its not possible to establish whether there is a selective deficit in learning (Von Engelhardt et al. 2008 Neuron)

5. What happens when NMDA receptors are knocked out in the hippocampus?

   • The NR1 subunit is obligatory for NMDA receptors. If the NR1 subunit is knocked out then there is no NMDA receptor.
     • Bannerman et al. 2012. Over trials of training mice were placed into the pool at locations that were nearer to the incorrect beacon or nearer to the correct beacon or equidistant between the two beacons. When released from a starting point that was equidistant between the two beacons the knockout mice were not impaired, demonstrating normal spatial learning. When released from a starting point near the incorrect beacon (S-) the knockout mice made more errors than the control mice. The knockout mice could not inhibit the response to approach the incorrect response. At the end of training the beacons and platform were removed a probe test was performed. The control and knockout mice showed a strong preference for the quadrant of the maze in which the platform was previously located.
       • Conclusion: NMDA receptors in the hippocampus are important for inhibiting responses to ambiguous cues (approaching a beacon is correct only 50% of the time). NMDA receptors do not appear to be essential for spatial learning. Is NMDA receptor-dependent LTP the neural mechanism for spatial learning? (possibly) no. Do NMDA receptors in the hippocampus play an important role in spatial behaviour? Yes

6. If the NMDA receptor-dependent LTP looks like its involved in coincidence detection why isn’t it necessary for associative learning? Shors and Matzel (1997) Long-term potentiation: what’s learning got to do with it? LTP may be a mechanism for arousal or attention

   • Gallistel and Matzel (2012) – LTP and learning are not similar. Timing of events: LTP – milliseconds; Associative learning – seconds, minutes, hours. Persistence: LTP is long lasting, but not long-term; Associative learning is long-term (lasts indefinitely). Reacquisition: Once LTP has decayed it takes just as much effort to reinstate; Associative learning is reacquired more rapidly than initial acquisition