Inhibition of CaMKII disrupts the formation of long term associative olfactory memory

De Jong, Jeremy (2009) Inhibition of CaMKII disrupts the formation of long term associative olfactory memory. Masters thesis, Memorial University of Newfoundland.

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Abstract

Calcium signaling is essential for the formation of mammalian associative memory, yet once in the cell the exact course of signaling taken by Ca²⁺ remains vague. The kinase known as CaMKII is highly attuned to bother the strength and frequency of Ca²⁺ influx and has been implicated in numerous memory paradigms. Moreover, its intrinsic autophosphorylating ability, which may be maintained up to an hour after Ca²⁺ influx, makes the kinase an extremely important molecule in the memory pathway. -- In the present study, I investigated the effect of inhibiting this kinase on olfactory preference learning in a neonate rat model. Normally, learning may be achieved by pairing isoproterenol (2 mg/kg) acting as an unconditioned stimulus with a conditioned stimulus odor, peppermint in this case, for 10 min. Here I found that infusion of KN-62 into the bulbs, a CaMKII inhibitor, 10 min before training as well as 10 and 30 min after training could disrupt normal 24 hr memory. Furthermore, I also used a non-learning dose if Iso (6 mg/kg) paired with odor, and found that in this group KN-62 infusion could induce learning. -- To confirm the role of CaMKII in this study we sacrificed animals at 5 min post-training to assay phosphorylated CaMKII levels and phosphorylated CREB levels. We also performed immunohistochemistry on animals sacrificed at 10 min post training to localize the effects of CaMKII and the distribution of the kinase in the olfactory bulb. -- Western blot analysis revealed that KN-62 reduced phosphorylated CaMKII levels in non-learning Iso 2(mg/kg) animals as hypothesized. Immunohistochemistry findings revealed a high CaMKII presence in the olfactory bulb, especially in the external plexiform layer and glomerular layer. KN-62 infusion decreased phosphorylated CaMKII expression in all layers of the olfactory bulb. -- In this study, we conclude that disruption of CaMKII during the early stages of memory consolidation, up to 30 min after training, in PND 6 rat pups may prevent the formation of long term memory.

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