Simulations suggest pharmacological methods for rescuing long-term potentiation

Abstract

Congenital cognitive dysfunctions are frequently due to deficits in molecular pathways that underlie the induction or maintenance of synaptic plasticity. For example, Rubinstein-Taybi syndrome (RTS) is due to a mutation in cbp, encoding the histone acetyltransferase CREB-binding protein (CBP). CBP is a transcriptional co-activator for CREB, and induction of CREB-dependent transcription plays a key role in long-term memory (LTM). In animal models of RTS, mutations of cbp impair LTM and late-phase long-term potentiation (LTP). As a step toward exploring plausible intervention strategies to rescue the deficits in LTP, we extended our previous model of LTP induction to describe histone acetylation and simulated LTP impairment due to cbp mutation. Plausible drug effects were simulated by model parameter changes, and many increased LTP. However no parameter variation consistent with a biochemical effect of a known drug class fully restored LTP. Thus we examined paired parameter variations consistent with effects of known drugs. A pair that simulated the effects of a phosphodiesterase inhibitor (slowing cAMP degradation) concurrent with a deacetylase inhibitor (prolonging histone acetylation) restored normal LTP. Importantly these paired parameter changes did not alter basal synaptic weight. A pair that simulated the effects of a phosphodiesterase inhibitor and an acetylase activator was similarly effective. For both pairs strong additive synergism was present. The effect of the combination was greater than the summed effect of the separate parameter changes. These results suggest that promoting histone acetylation while simultaneously slowing the degradation of cAMP may constitute a promising strategy for restoring deficits in LTP that may be associated with learning deficits in RTS. More generally these results illustrate how the strategy of combining modeling and empirical studies may provide insights into the design of effective therapies for improving long-term synaptic plasticity and learning associated with cognitive disorders.

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

“…Remarkably, CM-414 treatment did not affect the magnitude of LTP in APP/PS1 WT slices (Figure 2d and e). These results were consistent with earlier theoretical (Smolen et al, 2014) and experimental (Cuadrado-Tejedor et al, 2015) studies where a combination of HDAC and PDE inhibitors produced robust potentiation of synaptic transmission.…”

The right time to learn: mechanisms and optimization of spaced learning

“…For example, if simulated LTP deficits were rescued by combined parameter changes corresponding to known drug effects, these ‘best’ parameter combinations might prioritize drug combinations for testing in animal models. A recent study 104 took a first step by modelling LTP induction and transcriptional regulation by CREB, and simulating the effects of drugs on LTP by altering the parameters of the model. In this model, the magnitude of LTP induction was represented by an increase in a synaptic weight variable.…”

“…A CREB-binding protein ( Cbp ) mutation impairs hippocampal long-term potentiation (LTP) and impairs learning in mice, and Cbp +/− mice are considered to be a model for aspects of Rubinstein–Taybi syndrome in humans 104 . We developed a model to examine whether drugs could be used to overcome this impairment in LTP.…”

Superior long-term synaptic memory induced by combining dual pharmacological activation of PKA and ERK with an enhanced training protocol

“…Generally, the approach has been to focus on a single drug target such as histone deacetylase activity or AMPA receptor conductance (Alarcon et al 2004;Baudry et al 2012). However, targeting multiple pathways has clear advantages, allowing use of lower drug doses, which may reduce side effects (Smolen et al 2014;2016;Zhang et al 2014). Although activation of PKA has been shown to ameliorate LTP and LTM deficits in rodent disease models (Balakrishnan et al 2016;Bourtchouladze et al 2003), few if any attempts have been made to improve LTM by activating the ERK cascade alone or in combination with other pathways.…”