کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
4496119 1623850 2014 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Simulations suggest pharmacological methods for rescuing long-term potentiation
ترجمه فارسی عنوان
شبیه سازی ها روش های فارماکولوژیک را برای صرفه جویی در پتانسیل بلند مدت پیشنهاد می کنند
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم کشاورزی و بیولوژیک علوم کشاورزی و بیولوژیک (عمومی)
چکیده انگلیسی


• Modeling biochemical drug effects can suggest candidate combination therapies.
• We begin to apply this strategy to a congenital cause of cognitive disability.
• Dynamics of biochemical pathways underlying synaptic plasticity are simulated.
• Paired parameter changes similar to known drug effects rescue plasticity deficits.
• These simulations suggest possible interventions for Rubinstein–Taybi syndrome.

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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Theoretical Biology - Volume 360, 7 November 2014, Pages 243–250
نویسندگان
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