Behavioral consequences of calcium/calmodulin kinase II inhibition in rats
Schwartz, Elizabeth Ann
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CaM kinase II (CaMKII) comprises 2% of hippocampal protein and plays an important role in learning and models of neural plasticity. Previous studies have employed a variety of techniques to inhibit CaMKII to investigate its role. This includes the use of chemical inhibition, genetic mutation and antisense; all have shown limitations. In the present study, RNA interference (RNAi) was used to inhibit CaMKII in the hippocampus of rats. The goal of this project was to determine if inhibition of hippocampal CaM kinase would result in behavioral deficits consistent with the role of this kinase. Three behavioral tasks were used to assess behavioral changes associated with a lack of CaMKII in the hippocampus; an open-field task, water maze and T-maze task. An adeno-associated viral vector was used to deliver á CaMKII specific hairpins into rat hippocampi and cDNA for green fluorescent protein (GFP; marker protein). Control animals received AAV that encodes only GFP. In the open-field task, it was hypothesized that experimental rats would show changes in behavior consistent with impaired habituation. This hypothesis was supported; behaviors such as escape attempts and direct versus disorganized movement were significantly different between groups. In the water maze, it was hypothesized that experimental rats would show longer latencies to find the platform in the test phase and spend less time in the target quadrant than control rats during the probe trial. Groups did not differ significantly on latencies to the platform during the test phase but were different during the probe trial. This suggests that experimental rats may be using a non-spatial strategy to locate the platform. In the T-maze, it was hypothesized that the experimental rats would make more errors than control rats due to working memory deficits. This hypothesis was not supported. Densities of á and â subunit CaMKII bands were quantified from digitized images using a computerized densitometry program and á CaMKII was significantly reduced. GFP expression was localized to the hippocampus and extended ± 2 mm from the injection site. Intense áCaMKII staining was observed in control tissue, while staining in was markedly reduced in the experimental condition.