Modeling suggests combined-drug treatments for disorders impairing synaptic plasticity \textit{via} shared signaling pathways
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Publication:2137296
DOI10.1007/S10827-020-00771-4zbMATH Open1489.92070arXiv2010.11124OpenAlexW3100073704WikidataQ101567769 ScholiaQ101567769MaRDI QIDQ2137296FDOQ2137296
Authors: Paul Smolen, Marcelo A. Wood, Douglas A. Baxter, John H. Byrne 
Publication date: 16 May 2022
Published in: Journal of Computational Neuroscience (Search for Journal in Brave)
Abstract: Genetic disorders such as Rubinstein-Taybi syndrome (RTS) and Coffin-Lowry syndrome (CLS) cause lifelong cognitive disability, including deficits in learning and memory. Can pharmacological therapies be suggested to improve learning and memory in these disorders? To address this question, we simulated drug effects within a computational model describing induction of late long-term potentiation (L-LTP). Biochemical pathways impaired in these and other disorders converge on a common target, histone acetylation by acetyltransferases such as CREB binding protein (CBP), which facilitates gene induction necessary for L-LTP. We focused on four drug classes: tropomyosin receptor kinase B (TrkB) agonists, cAMP phosphodiesterase inhibitors, histone deacetylase inhibitors, and ampakines. Simulations suggested each drug type alone may rescue deficits in L-LTP. A potential disadvantage, however, was the necessity of simulating strong drug effects (high doses), which could produce adverse side effects. Thus, we investigated the effects of six drug pairs among the four classes described above. These combination treatments normalized impaired L-LTP with substantially smaller drug doses. In addition three of these combinations, a TrkB agonist paired with an ampakine and a cAMP phosphodiesterase inhibitor paired with a TrkB agonist or an ampakine, exhibited strong synergism in L-LTP rescue. Therefore, we suggest these drug combinations are promising candidates for further empirical studies in animal models of genetic disorders that impair acetylation, L-LTP, and learning.
Full work available at URL: https://arxiv.org/abs/2010.11124
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