Simulations suggest pharmacological methods for rescuing long-term potentiation

DOI10.1016/J.JTBI.2014.07.006zbMATH Open1343.92199arXiv1408.1921OpenAlexW2039226234WikidataQ42875495 ScholiaQ42875495MaRDI QIDQ739699FDOQ739699

Authors: Paul Smolen, Douglas A. Baxter, John H. Byrne 

Publication date: 19 August 2016

Published in: Journal of Theoretical Biology (Search for Journal in Brave)

Abstract: Congenital cognitive dysfunctions are frequently due to deficits in molecular pathways that underlie 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). To explore intervention strategies to rescue the deficits in LTP, we extended a previous model of LTP induction to describe histone acetylation and simulated LTP impairment due to cbp mutation. Plausible drug effects were simulated by parameter changes, and many increased LTP. However no parameter variation consistent with a biochemical effect of a known drug fully restored LTP. Thus we examined paired parameter variations. A pair that simulated the effects of a phosphodiesterase inhibitor (slowing cAMP degradation) concurrent with a deacetylase inhibitor (prolonging histone acetylation) restored LTP. Importantly these paired parameter changes did not alter basal synaptic weight. A pair that simulated a phosphodiesterase inhibitor and an acetyltransferase activator was similarly effective. For both pairs strong additive synergism was present. 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 the strategy of combining modeling and empirical studies may help design effective therapies for improving long-term synaptic plasticity and learning in cognitive disorders.

Full work available at URL: https://arxiv.org/abs/1408.1921

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zbMATH Keywords

long-term memorycombination therapycognitive disordersdrug synergismRubinstein-Taybi syndrome

Mathematics Subject Classification ID

Medical applications (general) (92C50) Kinetics in biochemical problems (pharmacokinetics, enzyme kinetics, etc.) (92C45)

Cited In (2)

• A multifarious exploration of synaptic tagging and capture hypothesis in synaptic plasticity: development of an integrated mathematical model and computational experiments
• Modeling suggests combined-drug treatments for disorders impairing synaptic plasticity \textit{via} shared signaling pathways

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