CaMKIIα mediates spermidine-induced memory enhancement in rats: A potential involvement of PKA/CREB pathway.

Memory consolidation is associated with the regulation of protein kinases, which impact synaptic functions and promote synaptogenesis. The administration of spermidine (SPD) has been shown to modulate major protein kinases associated with memory improvement, including the Ca2+-dependent protein kinase (PKC) and cAMP-dependent protein kinase (PKA), key players in the cAMP response element-binding protein (CREB) activation. Nevertheless, the initial mechanism underlying SPD-mediated memory consolidation remains unknown, as we hypothesize a potential involvement of the memory consolidation precursor, Ca2+/calmodulin-dependent protein kinase II-α (CaMKIIα), in this process. Based on this, our study aimed to investigate potential interactions among PKC, PKA, and CREB activation, mediated by CaMKIIα activation, in order to elucidate the SPD memory consolidation pathway. Our findings suggest that the post-training administration of the CaMKII inhibitor, KN-62 (0.25 nmol, intrahippocampal), prevented the memory enhancement induced by SPD (0.2 nmol, intrahippocampal) in the inhibitory avoidance task. Through western immunoblotting, we observed that phosphorylation of CaMKIIα in the hippocampus was facilitated 15 min after intrahippocampal SPD administration, resulting in the activation of PKA and CREB, 180 min after infusion, suggesting a possible sequential mechanism, since SPD with KN-62 infusion leads to a downregulation in CaMKIIα/PKA/CREB pathway. However, KN-62 does not alter the memory-facilitating effect of SPD on PKC, possibly demonstrating a parallel cascade in memory acquisition via PKA, without modulating CAMKIIα. These results suggest that memory enhancement induced by SPD administration involves crosstalk between CaMKIIα and PKA/CREB, with no PKC interaction.