  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.
