Role of galanin receptor 1 and galanin receptor 2 activation in synaptic plasticity associated with 3',5'-cyclic AMP response element-binding protein phosphorylation in the dentate gyrus: studies with a galanin receptor 2 agonist and galanin receptor 1 knockout mice.

The neuropeptide galanin was shown to impair cognitive performance and reduce hippocampal CA1 long-term potentiation (LTP) in rodents. However, the contribution of the two main galanin receptors; GalR1 and GalR2, present in the hippocampus to these effects is not known. In the present study, we determined the protein expression levels of GalR1 and GalR2 in the mouse dentate gyrus (DG) and used galanin (2-11), a recently introduced GalR2 agonist, and GalR1 knockout mice to examine the contribution of GalR1 and GalR2 to the modulation of LTP and 3',5'-cyclic AMP response element-binding protein (CREB)-dependent signaling cascades. In the DG, 57+/-5% of the galanin binding sites were GalR2, and the remaining population corresponded to GalR1. In hippocampal slices, galanin (2-11) fully blocked the induction of DG LTP, whereas galanin (1-29), a high affinity agonist for both GalR1 and GalR2, strongly but not fully attenuated the late phase of LTP by 80+/-1.5%. Application of galanin (1-29) or galanin (2-11) after LTP induction caused a transient reduction in the maintenance phase of LTP, with the larger effect displayed by superfusion of galanin (2-11). The induction and maintenance of DG LTP was not altered in the GalR1 knockout mice. Superfusion of galanin (1-29) or galanin (2-11) blocked the LTP induction to the same degree indicating a role for GalR2 in the induction phase of DG LTP. Furthermore, we analyzed the effects of GalR1 and/or GalR2 activation on DG LTP-induced CREB phosphorylation, associated with the late transcriptional effects of LTP. In the lateral part of the granule cell layer, high-frequency trains stimulation caused a significant increase in the level of CREB phosphorylation, which was significantly reduced by application of either galanin (1-29) or galanin (2-11), indicating that both GalR1 and/or GalR2 can mediate some of their effects on LTP through inhibition of CREB-related signaling cascades.