Role of hippocampal CaMKII in serotonin 5-HT(1A) receptor-mediated learning deficit in rats.

The serotonin 5-HT(1A) 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-HT(1A) 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-HT(1A) antagonist WAY-100635, indicating receptor-specific effects. We suggest that 5-HT(1A) 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-HT(1A) receptors.

Citation

Sonia Moyano, Joaquín Del Río, Diana Frechilla. Role of hippocampal CaMKII in serotonin 5-HT(1A) receptor-mediated learning deficit in rats. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2004 Dec;29(12):2216-24

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PMID: 15199370

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