Serotonin 5-HT1A receptor blockade enhances Ca2+/calmodulin-dependent protein kinase II function and membrane expression of AMPA receptor subunits in the rat hippocampus:: implications for memory formation

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-HT1A 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.