Improved Long-Term Memory via Enhancing cGMP-PKG Signaling Requires cAMP-PKA Signaling

Abstract

Memory consolidation is defined by the stabilization of a memory trace after acquisition, and consists of numerous molecular cascades that mediate synaptic plasticity. Commonly, a distinction is made between an early and a late consolidation phase, in which early refers to the first hours in which labile synaptic changes occur, whereas late consolidation relates to stable and long-lasting synaptic changes induced by de novo protein synthesis. How these phases are linked at a molecular level is not yet clear. Here we studied the interaction of the cyclic nucleotide-mediated pathways during the different phases of memory consolidation in rodents. In addition, the same pathways were studied in a model of neuronal plasticity, long-term potentiation (LTP). We demonstrated that cGMP/protein kinase G (PKG) signaling mediates early memory consolidation as well as early-phase LTP, whereas cAMP/protein kinase A (PKA) signaling mediates late consolidation and late-phase-like LTP. In addition, we show for the first time that early-phase cGMP/PKG signaling requires late-phase cAMP/PKA-signaling in both LTP and long-term memory formation.

Possible overlapping time frames of acquisition and consolidation phases in object memory processes: a pharmacological approach

“…Rolipram only fully reversed the scopolamine-induced deficit when injected at 2 min after T1, but an intermediate effect was found when rolipram was injected immediately after T1, that is, the d2 index of rats injected at 0 min after T1 was higher compared to zero but not compared to vehicle-treated animals after 24 h. Also in the 24-h retention interval, an intermediate effect of rolipram treatment was found within the first 2 min after T1. In previous studies we never found that rolipram was effective when injected directly after T1 using a 24-h delay interval (Rutten et al 2006(Rutten et al , 2007(Rutten et al , 2009Bollen et al 2014). However, in those studies our injection times were on average about 4 -10 min after the acquisition trial due to the injection procedures including taking the rat from the apparatus and taking the injection needle(s) (see Bollen et al 2014).…”

“…In previous studies we never found that rolipram was effective when injected directly after T1 using a 24-h delay interval (Rutten et al 2006(Rutten et al , 2007(Rutten et al , 2009Bollen et al 2014). However, in those studies our injection times were on average about 4 -10 min after the acquisition trial due to the injection procedures including taking the rat from the apparatus and taking the injection needle(s) (see Bollen et al 2014).…”

“…The present data provide further support that enhancing effects of vardenafil on memory consolidation processes can be found up to 50 min after T1 (taking into account the injection interval and brain penetration). The effect of vardenafil on consolidation processes is likely to be mediated via glutamatergic stimulation of post-synaptic GMP/PKG signaling (Lu et al 1999;Bollen et al 2014).…”

“…On the other hand, phosphodiesterase type 5 inhibitors (PDE5-Is) affect acquisition and early consolidation processes via an increase in intracellular cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) signaling, when administered before or directly after learning, respectively (Devan et al 2004(Devan et al , 2007Prickaerts et al 2005;Domek-Lopacinska and Strosznajder 2008;van Donkelaar et al 2008;Bollen et al 2014). Also, we found that the phosphodiesterase type 4 inhibitor (PDE4-I) rolipram, which increases cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling, improves both acquisition and late consolidation processes when administered before or at 3 h after learning (Rutten et al 2006(Rutten et al , 2007Bollen et al 2014). These findings provide further support for the notion that acquisition and consolidation processes can be associated with dissociable neurobiological processes.…”

Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach

“…NO also mediates CREB-DNA binding via a Ser133-independent mechanism by the S-nitrosylation of nuclear proteins associated with CREB target genes [96]. Various studies have suggested that NO/cGMP/PKG and cAMP/PKA cooperate to ensure different phases of LTP and to underpin memory acquisition and consolidation via CREB phosphorylation [94,[97][98][99][100]. CREB phosphorylation is now recognized as a crucial event that regulates transcription during synaptic plasticity [101][102][103], leading to protein synthesis and the generation of new dendritic spines to ensure longterm morphological changes associated with late LTP [104].…”