title: Rescue of impaired long-term facilitation at sensorimotor synapses of Aplysia following siRNA knockdown of CREB1.
abstract: Memory impairment is often associated with disrupted regulation of gene induction. For example, deficits in cAMP response element-binding protein (CREB) binding protein (CBP; an essential cofactor for activation of transcription by CREB) impair long-term synaptic plasticity and memory. Previously, we showed that small interfering RNA (siRNA)-induced knockdown of CBP in individual sensory neurons significantly reduced levels of CBP and impaired 5-HT-induced long-term facilitation (LTF) in sensorimotor cocultures from Aplysia. Moreover, computational simulations of the biochemical cascades underlying LTF successfully predicted training protocols that restored LTF following CBP knockdown. We examined whether simulations could also predict a training protocol that restores LTF impaired by siRNA-induced knockdown of the transcription factor CREB1. Simulations based on a previously described model predicted rescue protocols that were specific to CREB1 knockdown. Empirical studies demonstrated that one of these rescue protocols partially restored impaired LTF. In addition, the effectiveness of the rescue protocol was enhanced by pretreatment with rolipram, a selective cAMP phosphodiesterase inhibitor. These results provide further evidence that computational methods can help rescue disruptions in signaling cascades underlying memory formation. Moreover, the study demonstrates that the effectiveness of computationally designed training protocols can be enhanced with complementary pharmacological approaches.
authors: Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston, Houston, Texas 77030.
authors: Lian
authors: L
authors: Zhou
authors: Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston, Houston, Texas 77030.
authors: Yili
authors: http://orcid.org/0000-0003-4272-494X
authors: Y
authors: Zhang
authors: Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston, Houston, Texas 77030.
authors: Rong-Yu
authors: RY
authors: Liu
authors: Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston, Houston, Texas 77030.
authors: Paul
authors: P
authors: Smolen
authors: Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston, Houston, Texas 77030.
authors: Leonard J
authors: http://orcid.org/0000-0002-7656-0798
authors: LJ
authors: Cleary
authors: Department of Neurobiology and Anatomy, The University of Texas Medical School at Houston, Houston, Texas 77030 John.H.Byrne@uth.tmc.edu.
authors: John H
authors: JH
authors: Byrne
mesh_terms: D000818:Animals; D001048:Aplysia / Q000166:cytology; D001703:Biophysics; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018920:Coculture Techniques; D003198:Computer Simulation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008959:Models, Neurological; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors
chemical_list: D034741:RNA, Small Interfering; D012701:Serotonin; D050882:CREB-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases
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