O1‐04–05: Chronic lithium treatment magnifies learning and enhances LTP in area CA1 of the hippocampus

Recent electrophysiological work shows that chronic lithium treatment increases hippocampal long-term potentiation (LTP; Son et al., 2003, Yu et al., 2003; Shim et al., 2006), the major neurophysiological basis for the development of learning and memory. Chronic lithium also upregulates neurotrophic factors that are involved in the expression of LTP (Einat et al., 2003). These studies suggest that lithium might enhance learning and memory. However, few studies have assessed the effects of lithium on learning. We used three different positive reinforcement spatial cognitive tasks to determine the effects of chronic lithium treatment on learning in rats. Each task differed in complexity, in the type of learning required (instrumental or associative), and in the reward received. To provide stable, clinically relevant levels of lithium throughout testing, a lithium chow diet was used. We also assessed the effect of the lithium diet on LTP of pyramidal cells in area CA1 of hippocampal slices, an area strongly implicated in the pathophysiology of Alzheimer's disease. Socially housed rats were given continual access to lithium chow or to a control chow diet for four weeks prior to, and throughout all learning assessments. After four weeks access to their designated chow diet, rats began conditioning in the holeboard spatial discrimination or t-maze delayed alternation task. They immediately began conditioning in the opposite task once completing the first. This was then followed with social place-preference conditioning, after 24-hours isolation from their homecage social partner. Results showed that chronic lithium magnified learning in all three paradigms, regardless of the reward received. Both food and social interaction supported enhanced learning. Furthermore, four weeks exposure to the lithium diet also enhanced LTP in area CA1 of hippocampal slices prepared from the rats fed with the lithium chow. This enhancement was shown under clinically relevant serum levels at the time of testing (0.70 ± 0.03 mEq/l). These findings suggest that chronic lithium treatment may improve cognitive function in Alzheimer's disease by enhancing mechanisms involved in basal learning and memory formation, such as hippocampal LTP.