Role of Hippocampal CaMKII in Serotonin 5-HT1A Receptor-Mediated Learning Deficit in Rats

The serotonin 5-HT1A receptor agonist, 8-OH-DPAT (8-hydroxy-2-di-n-propylamino-tetralin), impairs retention performance in a passive avoidance learning task in rats. In the hippocampus of rats trained on this procedure and killed 1 h after the acquisition trial, an increase in the membrane levels of both Ca2+/calmodulin-dependent protein kinase II (CaMKII) and phosphorylated CaMKII, as well as in total and Ca2+-independent enzyme activity in tissue lysates was found. These effects were learning-specific as no changes in CaMKII levels or activity were found in rats receiving a footshock identical to the trained rats. The effect of training on CaMKII was prevented by a low 8-OH-DPAT dose. The 5-HT1A agonist also reduced protein kinase A (PKA) activity and increased the membrane levels of phosphatase 1 (PP1) and PP1 enzyme activity in the hippocampus. All of the changes induced by 8-OH-DPAT were reversed by the selective 5-HT1A antagonist WAY-100635, indicating receptor-specific effects. We suggest that 5-HT1A receptor-mediated disruption of retention performance is a consequence of the reduced PKA activity and the ensuing enhancement in PP1 activity, possibly through decreased phosphorylation/activation of endogenous PP1 inhibitors, that cause a reduced activity of phosphorylated CaMKII, a key enzyme in early stages of memory formation. This study provides an in vivo molecular basis for the cognitive deficits induced by stimulation of hippocampal 5-HT1A receptors.