Our memories are fundamental components of who we are as individuals. They influence almost every aspect of our lives such as our decisions, our personalities, our emotions, and our purpose in life. Diseases that affect memory have devastating impacts on the individuals who bear them. Imagine not being able to recall pleasant memories or even the faces of close family members. It's important to understand the biology of memory formation not only because it's an intriguing scientific question, but because of its consequences when these processes are lost. N-methyl-D-aspartate-type glutamate receptors (NMDARs) and calcium/calmodulin-dependent kinase II (CaMKII) are essential molecules involved in learning and its physiological correlate, synaptic plasticity. Calcium influx through NMDARs activates CaMKII, which translocates to the postsynaptic signaling sites through its interactions with the NMDAR subunits NR1 and NR2B. The significance of CaMKII's translocation is not fully known, however we hypothesize that it is an early molecular event that is necessary for the expression of synaptic plasticity and learning. Our laboratory has developed two strains of mice with targeted mutations to NR1 and NR2B (NR1KI and NR2BKI) that are deficient in their ability to bind to CaMKII to test the role of CaMKII binding to NMDARs in synaptic plasticity and learning. We found that CaMKII binding to NR2B is necessary for long-term potentiation (LTP), the most commonly studied form of synaptic plasticity. NR2BKI mice are able to learn spatial and cued tasks normally, however they are unable to consolidate spatial tasks for long-term memory storage. On the other hand, we found that CaMKII binding to NR1 is not necessary for LTP. Furthermore NR1KI mice do not show impairments in contextual or cued learning. We found that NR1 mutations resulted in an age-dependent truncation of the intracellular domains of NR1 that reduced its activity leading to severe impairments in synaptic transmission, LTP, and learning. Our results suggest that CaMKII binding to NR2B is the more important for synaptic plasticity and memory formation than NR1. However, we found that the intracellular domains of NR1 are critical for NMDAR and synapse function.
| Identifer | oai:union.ndltd.org:uiowa.edu/oai:ir.uiowa.edu:etd-1668 |
| Date | 01 May 2010 |
| Creators | Dallapiazza, Robert Francis |
| Contributors | Hell, Johannes W. |
| Publisher | University of Iowa |
| Source Sets | University of Iowa |
| Language | English |
| Detected Language | English |
| Type | dissertation |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | Copyright 2010 Robert Francis Dallapiazza |
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