Serotonin 5-HT1A receptor blockade enhances Ca 2+/calmodulin-dependent protein kinase II function and membrane expression of AMPA receptor subunits in the rat hippocampus: Implications for memory formation

Abstract

Stimulation of hippocampal 5-HT1A receptors impairs memory retention. The highly selective 5-HT1A antagonist, WAY-100635, prevents the cognitive deficits induced not only by 5-HT-1A stimulation but also by cholinergic or NMDA receptor blockade. On this basis, the effects of WAY-100635 on. molecular events associated with memory storage were explored. In rat hippocampus, WAY-100635 produced a rapid increase in phosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII) and in Ca2+-independent CaMKII and protein kinase A (PKA) enzyme activity. This increase was followed a few hours later by an enhanced membrane expression of AMPA receptor subunits, especially of the GluR1 subunit phosphorylated at the CaMKII site, pGluR1-(Ser831). The same qualitative effects were found with the weaker 5-HT1A antagonist NAN-190. The effects of both antagonists were no longer apparent in rats with a previous 5-HT depletion induced by the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA), suggesting that 5-HT1A receptor blockade removes the tonic inhibition of 5-HT through 5-HT1A receptor stimulation on excitatory hippocampal neurons, with the consequent increase in PKA activity. In addition, administration of WAY-100635 potentiated the learning-specific increase in the hippocampus of phospho-CaMKII, Ca2+-independent CaMKII activity, as well as the phosphorylation of either the CaMKII or the PKA site on the AMPA receptor GluR1 subunit. This study suggests that blockade of hippocampal 5-HT1A receptors favours molecular events critically involved in memory formation, and provides an in vivo molecular basis for the proposed utility of 5-HT1A receptor antagonists in the treatment of cognitive disorders. © 2005 International Society for Neurochemistry.