Andrew Wallmann and Dr. Jeff Edwards, Physiology and Developmental Biology

Until recently, our understanding of the molecular mechanisms behind memory has been extremely limited. However, recent studies indicate that memory formation is associated with two forms of neuronal plasticity known as long-term potentiation (LTP) and long-term depression (LTD) (Bailey & Kandel, 2008). These are physiological processes that essentially alter the strength of a synapse between two neurons and are of particular importance in the brain region called the hippocampus. The hippocampus is heavily associated with learning and memory and is a frequent target of research for this reason. A novel form of LTP has recently been found within the hippocampus that implements a receptor protein called TRPV1 (Gibson, Edwards, Page, Van Hook, & Kauer, 2008). TRPV1 has been connected to a number of functions within the peripheral nervous system (PNS), but this finding is one of the first to implicate TRPV1 with functions inside the central nervous system.

This project was aimed at advancing our knowledge of the role that TRPV1 plays in the circuitry behind LTP in the CA1 region of the hippocampus. By selectively activating and inhibiting TRPV1 in combination with the inhibition of interneuron activity, we sought to provide evidence for our working model of the circuitry involved in this form of plasticity. The hope of this project was that increased understanding of what is occurring at the molecular level of these neurons would then open up new doors in research being done to develop innovative therapies that combat memory deficits. Of particular interest is the consequence that such research could have for diseases such as Alzheimer’s and other related neurodegenerative diseases. These diseases frequently show impairments in hippocampal plasticity (Houeland et al., 2010), but treatment options to counteract these effects will remain ineffective until we understand the mechanisms that are being impaired.

Data for this project was obtained primarily through analysis of electrophysiological recordings that record the electrical activities of neurons in response to drugs and stimulation protocols. The stimulation protocols act to mimic activity in the brain by activating the neurons and generating action potentials that can then generate a response at various synapses that can be recorded. By recording these responses at specific regions of the hippocampus while simultaneously activating or deactivating select proteins with drugs, we were able to determine the role that these proteins played in the electrophysiology of the hippocampus.

During the course of the project the majority of the experimental designs ran smoothly and without incident. However, an obstacle was encountered with the use of the drug picrotoxin, a noncompetitive GABAA antagonist. For unknown reasons, solutions that were prepared with the inclusion of this drug failed to elicit the desired LTP that had previously been seen using the same protocol. Since the drug had been used successfully at the onset of the project, some sort of contamination of the equipment was suspected. However, cleaning or replacing of all pieces of equipment used failed to resolve the problem. A number of additional solutions were attempted, such as varying the concentration of the drug, but ultimately the issue was resolved by replacing the drug with a second GABAA antagonist, bicuculline. Once this solution was implemented, all procedures continued to run smoothly to the conclusion of the project.

The results from these experiments provided strong evidence for our working model of the circuitry involved in this form of plasticity. As our model proposes, TRPV1 appears to be involved in modulating hippocampal plasticity at the CA3-CA1 synapse, a major synapse in the hippocampus. Our results focused primarily on the effects that TRPV1 activation has on the potentiation or strengthening of the synapse in question, but the next project needed in this area of research is determine the role that TRPV1 plays in the depression or weakening of this same synapse. Our lab is currently undertaking this project, but we are still in the process of designing the necessary experimental protocols.

The project was successfully brought to a close and the results have been published and presented at a number of conferences. The data from the experiments was written up and published in the September issue of Neuropharmacology (Bennion et al., 2011) and the abstract has been published at all of the conferences where a poster of the data was presented. These conferences include the Marie Lou Foulton conference hosted at BYU, the Intermoutain chapter of the Society for Neuroscience Snowbird conferece, and the 2011 international conference for the Society for Neuroscience. An oral presentation of the research was also presented at the Utah Conference for Undergraduate Research.

References

• Bailey, C. H., & Kandel, E. R. (2008). Synaptic remodeling, synaptic growth and the storage of long-term memory in aplysia. Essence of Memory, 169, 179-198. doi:10.1016/S0079-6123(07)00010-6
• Bennion, D., Jensen, T., Walther, C., Hamblin, J., Wallmann, A., Couch, J., . . . Edwards, J. G. (2011). Transient receptor potential vanilloid 1 agonists modulate hippocampal CA1 LTP via the GABAergic system.Neuropharmacology, 61(4), 730-738. doi:10.1016/j.neuropharm.2011.05.018
• Gibson, H. E., Edwards, J. G., Page, R. S., Van Hook, M. J., & Kauer, J. A. (2008). TRPV1 channels mediate long-term depression at synapses on hippocampal interneurons. Neuron, 57(5), 746-759. doi:10.1016/j.neuron.2007.12.027
• Houeland, G., Romani, A., Marchetti, C., Amato, G., Capsoni, S., Cattaneo, A., & Marie, H. (2010). Transgenic mice with chronic NGF deprivation and alzheimer’s disease-like pathology display hippocampal region-specific impairments in short- and long-term plasticities. Journal of Neuroscience, 30(39), 13089-13094. doi:10.1523/JNEUROSCI.0457-10.2010