Simulations suggest pharmacological methods for rescuing long-term potentiation
Open accessAbstract
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 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 acetyltransferase 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.
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LTP impairment seen in a mouse model of RTS was first simulated.
“LTP impairment seen in a mouse model of RTS95 was first simulated.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [104]
A recent study 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.
“A recent study104 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.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [104]
No single-drug effect completely rescued LTP.
“However, no single-drug effect completely rescued LTP.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [104]
The second pair corresponded to a PDE inhibitor paired with a deacetylase inhibitor.
“The second pair corresponded to a PDE inhibitor paired with a deacetylase inhibitor.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [104]
In the first case, an increased rate constant for histone acetylation, corresponding to application of an acetyltransferase activator, was paired with an increased duration of stimulus-induced increase in cAMP levels, corresponding to application of a cAMP phosphodiesterase (PDE) inhibitor.
“In the first case, an increased rate constant for histone acetylation, corresponding to application of an acetyltransferase activator, was paired with an increased duration of stimulus-induced increase in cAMP levels, corresponding to application of a cAMP phosphodiesterase (PDE) inhibitor.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [104]
Two pairs of parameter changes, corresponding to plausible paired-drug effects, were identified that restored LTP.
“Thus, pairs of parameter changes were considered, corresponding to plausible paired-drug effects. Two pairs were identified that restored LTP.”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [104]
For both pairs, additive drug synergism, defined as a combined-drug effect that exceeds the summed effects of the individual drugs, was evident, as quantified by a simple additive measure.
“For both pairs, additive drug synergism, defined as a combined-drug effect that exceeds the summed effects of the individual drugs, was also evident, as quantified by a simple additive measure (FIG. 5).”
From The right time to learn: Mechanisms and optimization of spaced learning (2016) · cites this paper as [104]
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- Authors
- Smolen, P., Baxter, D. A., & Byrne, J. H.
- Corresponding author
- Smolen, Paul
- Venue
- Journal of Theoretical Biology
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 360
- Pages
- 243-250
- ISSN
- 0022-5193 (ISSN-L)
- PMC
- PMC4162763
- OpenAlex
- W2039226234
- Cited by
- 13
- References
- 57
- Citations by year
- 2025: 1 · 2022: 2 · 2020: 3 · 2019: 1 · 2017: 3 · 2016: 2 · 2015: 1
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Theoretical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- arXiv (Cornell University) (submittedVersion)
- arXiv (Cornell University)
- Funders
- NIH (R01 NS073974)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- long-term potentiation, Rubinstein-Taybi syndrome, CREB-binding protein, histone acetylation, cAMP degradation, phosphodiesterase inhibitors, histone deacetylase inhibitors, drug synergy, synaptic plasticity, long-term memory, cognitive impairment
- MeSH terms
- Computer Simulation, Drug Synergism, Humans, Models, Biological, Mutation, Neuronal Plasticity, Peptide Fragments, Phosphodiesterase Inhibitors, Rubinstein-Taybi Syndrome, Sialoglycoproteins, Long-Term Potentiation, Metabolic Networks and Pathways, Histone Deacetylase Inhibitors
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