Skip to main content

Advertisement

SpringerLink
Log in

Modeling suggests combined-drug treatments for disorders impairing synaptic plasticity via shared signaling pathways

  • Published:
Journal of Computational Neuroscience Aims and scope Submit manuscript

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 that 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 individual 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 histone acetylation, L-LTP, and learning.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Agell, N., Bachs, O., Rocamora, N., & Villalonga, P. (2002). Modulation of the Ras/Raf/MEK/ERK pathway by Ca2+ and calmodulin. Cellular Signalling, 14, 649–654.

    CAS  PubMed  Google Scholar 

  • Ahmed, T., & Frey, J. U. (2005). Plasticity-specific phosphorylation of CaMKII, MAP-kinases, and CREB during late-LTP in hippocampal slices in vitro. Neuropharmacology, 49, 477–492.

    CAS  PubMed  Google Scholar 

  • Aizawa, H., Hu, S. C., Bobb, K., Balakrishnan, K., Ince, G., Gurevich, I., Cowan, M., & Ghosh, A. (2004). Dendrite development regulated by CREST, a calcium-regulated transcriptional activator. Science, 30, 197–202.

    Google Scholar 

  • Alarcon, J. M., Malleret, G., Touzani, K., Vronskaya, S., Ishii, S., Kandel, E. R., & Barco, A. (2004). Chromatin acetylation, memory, and LTP are impaired in CBP(+/−) mice: A model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron, 42, 947–959.

    CAS  PubMed  Google Scholar 

  • Andreska, T., Rauskolb, S., Schukraft, N., Luningschror, P., Sasi, M., et al. (2020). Induction of BDNF expression in layer II/III and layer V neurons of the motor cortex is essential for motor learning. The Journal of Neuroscience, 40, 6289–6308.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Anium, R., & Blenis, J. (2008). The RSK family of kinases: Emerging roles in cellular signaling. Nature Reviews. Molecular Cell Biology, 9, 747–758.

    Google Scholar 

  • Arai, A. C., & Kessler, M. (2007). Pharmacology of ampakine modulators: From AMPA receptors to synapses and behavior. Curr. Drug Targets, 8, 583–602.

    CAS  Google Scholar 

  • Bambah-Mukku, D., Travaglia, A., Chen, D. Y., Pollonini, G., & Alberini, C. M. (2014). A positive autoregulatory BDNF feedback loop via C/EBPβ mediates hippocampal memory consolidation. The Journal of Neuroscience, 34, 12547–12559.

    PubMed  PubMed Central  Google Scholar 

  • Barco, A., Alarcon, J. M., & Kandel, E. R. (2002). Expression of constitutively active CREB facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell, 108, 689–703.

    CAS  PubMed  Google Scholar 

  • Baudry, M., Kramar, E., Xu, X., Zadran, H., Moreno, S., Lynch, G., Gall, C., & Bi, X. (2012). Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome. Neurobiology of Disease, 47, 210–215.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Barrera, N. P., Morales, B., Torres, S., & Villalon, M. (2005). Principles, mechanisms, and modeling of synergism in cellular responses. Trends in Pharmacological Sciences, 26, 526–532.

    CAS  PubMed  Google Scholar 

  • Berenbaum, M. (1989). What is synergy? Pharmacological Reviews, 41, 93–141.

    CAS  PubMed  Google Scholar 

  • Bhalla, U. S., & Iyengar, R. (1999). Emergent properties of networks of biological signaling pathways. Science, 283, 381–387.

    CAS  PubMed  Google Scholar 

  • Bijnsdorp, I. V., Giovannetti, E., & Peters, G. J. (2011). Analysis of drug interactions. Methods in Molecular Biology, 731, 421–434.

    CAS  PubMed  Google Scholar 

  • Bjornsson, H. T., Benjamin, J. S., Zhang, L., Weissman, J., Gerber, E. E., Chen, Y. C., Vaurio, R. G., Potter, M. C., Hansen, K. D., & Dietz, H. C. (2014). Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of kabuki syndrome. Sci. Transl. Med., 6, 256ra135.

    PubMed  PubMed Central  Google Scholar 

  • Bliss, C. I. (1939). The toxicity of poisons applied jointly. The Annals of Applied Biology, 26, 585–615.

    CAS  Google Scholar 

  • Boran, A. D. W., & Iyengar, R. (2010). Systems approaches to polypharmacology and drug discovery. Current Opinion in Drug Discovery & Development, 13, 297–309.

    CAS  Google Scholar 

  • Bourtchouladze, R., Lidge, R., Catapano, R., Stanley, J., Gossweiler, S., Romashko, D., Scott, R., & Tully, T. (2003). A mouse model of Rubinstein-Taybi syndrome: Defective long-term memory is ameliorated by inhibitors of PDE 4. Proc. Natl. Acad. Sci. USA, 100, 10518–10522.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bradshaw, J. M., Kubota, Y., Meyer, T., & Schulman, H. (2003). An ultrasensitive Ca2+/calmodulin-dependent protein kinase II-protein phosphatase 1 switch facilitates specificity in postsynaptic calcium signaling. Proc. Natl. Acad. Sci. USA, 100, 10512–10517.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cammarota, M., Bevilaqua, L. R., Ardenghi, P., Paratcha, G., Levi de Stein, M., Izquierdo, I., & Medina, J. H. (2000). Learning-associated activation of nuclear MAPK, CREB and Elk-1, along with Fos production, in the rat hippocampus after a one-trial avoidance learning: Abolition by NMDA receptor blockade. Molecular Brain Research, 76, 36–46.

    CAS  PubMed  Google Scholar 

  • Chen, D. Y., Bambah-Mukku, D., Pollonini, G., & Alberini, C. M. (2012). Glucocorticoid receptors recruit the CaMKIIα-BDNF-CREB pathways to mediate memory consolidation. Nature Neuroscience, 15, 1707–1714.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen, P. B., Kawaguchi, R., Blum, C., Achiro, J. M., Coppola, G., O’Dell, T. J., & Martin, K. C. (2017). Mapping gene expression in excitatory neurons during hippocampal late-phase long-term potentiation. Frontiers in Molecular Neuroscience, 10, 39.

    PubMed  PubMed Central  Google Scholar 

  • Chrivia, J. C., Kwok, R. P., Lamb, N., Hagiwara, M., Montminy, M. R., & Goodman, R. H. (1993). Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature, 365, 855–859.

    CAS  PubMed  Google Scholar 

  • Cogne, B., Ehresmann, S., Beauregard-Lacroix, E., Rousseau, J., Besnard, T., et al. (2019). Missense variants in the histone acetyltrasferase complex component gene TRRAP cause autism and syndromic intellectual disability. American Journal of Human Genetics, 104, 530–541.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Colgan, L. A., Hu, M., Misler, J. A., Parra-Bueno, P., Moran, C. M., Leitges, M., & Yasuda, R. (2018). PKCα integrates spatiotemporally distinct Ca2+ and autocrine BDNF signaling to facilitate synaptic plasticity. Nature Neuroscience, 21, 1027–1037.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cuadrado-Tejedor, M., Garcia-Barroso, C., Sanzhez-Arias, J., Mederos, S., Rabal, O., Ugarte, A., Franco, R., Pascual-Lucas, M., Segura, V., Perea, G., Oyarzabal, J., & Garcia-Osta, A. (2015). Concomitant histone deacetylase and phosphodiesterase 5 inhibition synergistically prevents the disruption in synaptic plasticity and reverses cognitive impairment in a mouse model of Alzheimer’s disease. Clinical Epigenetics, 7, 108.

    CAS  PubMed  PubMed Central  Google Scholar 

  • De Cesare, D., Fimia, G. M., & Sassone-Corsi, P. (1999). Signaling routes to CREM and CREB: Plasticity in transcriptional activation. Trends in Biochemical Sciences, 24, 281–285.

    PubMed  Google Scholar 

  • Delaunoy, J. P., Dubos, A., Marques Pereira, P., & Hanauer, A. (2006). Identification of novel mutations in the RSK2 gene (RPS6Ka3) in patients with coffin-Lowry syndrome. Clinical Genetics, 70, 161–166.

    CAS  PubMed  Google Scholar 

  • Ehninger, D., & Silva, A. J. (2011). Rapamycin for treating tuberous sclerosis and autism spectrum disorders. Trends in Molecular Medicine, 17, 78–87.

    CAS  PubMed  Google Scholar 

  • English, J. D., & Sweatt, J. D. (1997). A requirement for the mitogen-activated protein kinase cascade in hippocampal long-term potentiation. The Journal of Biological Chemistry, 272, 19103–19106.

    CAS  PubMed  Google Scholar 

  • Foucquier, J., & Guedj, M. (2015). Analysis of drug combinations: Current methodological landscape. Pharmacology Research & Perspectives, 3, e00149.

    Google Scholar 

  • Frank, P. M. (1978). Introduction to system sensitivity theory. Academic Press, New York., 9–10.

  • Frey, U., & Morris, R. G. (1997). Synaptic tagging and long-term potentiation. Nature, 385, 533–536.

    CAS  PubMed  Google Scholar 

  • Frey, U., & Morris, R. G. (1998). Synaptic tagging: Implications for late maintenance of hippocampal long-term potentiation. Trends in Neurosciences, 21, 181–188.

    CAS  PubMed  Google Scholar 

  • Gao, L., Tian, M., Zhao, H. Y., Xu, Q. Q., Huang, Y. M., Si, Q. C., Tian, Q., Wu, Q. M., Hu, X. M., Sun, L. B., McClintock, S. M., & Zeng, Y. (2016). TrkB activation by 7, 8-dihydroxyflavone increases synapse AMPA subunits and ameliorates spatial memory deficits in a mouse model of Alzheimer’s disease. Journal of Neurochemistry, 136, 620–636.

    CAS  PubMed  Google Scholar 

  • Guedea, A. L., Schrick, C., Guzman, Y. F., Leaderbrand, K., Jovasevic, V., Corcoran, K. A., Tronson, N. C., & Radulovic, J. (2011). ERK-associated changes of AP-1 proteins during fear extinction. Molecular and Cellular Neurosciences, 47, 137–144.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Guilding, C., McNair, K., Stone, T. W., & Morris, B. J. (2007). Restored plasticity in a mouse model of neurofibromatosis type 1 via inhibition of hyperactive ERK and CREB. The European Journal of Neuroscience, 25, 99–105.

    PubMed  Google Scholar 

  • Hayer, A., & Bhalla, U. S. (2005). Molecular switches at the synapse emerge from receptor and kinase traffic. PLoS Computational Biology, 1, 137–154.

    CAS  PubMed  Google Scholar 

  • Herberg, F. W., Taylor, S. S., & Dostmann, W. R. (1996). Active site mutations define the pathway for the cooperative activation of cAMP-dependent protein kinase. Biochemistry, 35, 2934–2942.

    CAS  PubMed  Google Scholar 

  • Hernandez, A. I., Blace, N., Crary, J. F., Serrano, P. A., Leitges, M., Libien, J. M., Weinstein, G., Tcherapanov, A., & Sacktor, T. C. (2003). Protein kinase M ζ synthesis from a brain mRNA encoding an independent protein kinase C ζ catalytic domain. Implications for the molecular mechanism of memory. J. Biol. Chem., 278, 40305–40316.

    CAS  PubMed  Google Scholar 

  • Hevroni, D., Rattner, A., Bundman, M., Lederfein, D., Gabarah, A., Mangelus, M., Silverman, M. A., Kedar, H., Naor, C., Kornuc, M., Hanoch, T., Seger, R., Theill, L. E., Nedivi, E., Richter-Levin, G., & Citri, Y. (1998). Hippocampal plasticity involves extensive gene induction and multiple cellular mechanisms. Journal of Molecular Neuroscience, 10, 75–98.

    CAS  PubMed  Google Scholar 

  • Hsieh, C., Tsokas, P., Serrano, P., Hernández, A. I., Tian, D., Cottrell, J. E., Shouval, H. Z., Fenton, A. A., & Sacktor, T. C. (2017). Persistent increased PKMζ in long-term and remote spatial memory. Neurobiology of Learning and Memory, 138, 135–144.

    CAS  PubMed  Google Scholar 

  • Huang, Y. Y., & Kandel, E. R. (1995). D1 / D5 receptor agonists induce a protein synthesis-dependent late phase in the CA1 region of hippocampus. Proc. Natl. Acad. Sci. USA, 92, 2446–2450.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Impey, S., Fong, A. L., Wang, Y., Cardinaux, J. R., Fass, D. M., Obrietan, K., Wayman, G. A., Storm, D. R., Soderling, T. R., & Goodman, R. H. (2002). Phosphorylation of CBP mediates transcriptional activation by neural activity and CaM kinase IV. Neuron, 34, 235–244.

    CAS  PubMed  Google Scholar 

  • Kazantsev, A. G., & Thompson, L. M. (2008). Therapeutic application of deacetylase inhibitors for central nervous system disorders. Nature Reviews. Drug Discovery, 7, 854–868.

    CAS  PubMed  Google Scholar 

  • Kelly, M. T., Crary, J. F., & Sacktor, T. C. (2007). Regulation of protein kinase Mζ synthesis by multiple kinases in long-term potentiation. The Journal of Neuroscience, 27, 3439–3444.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Komiyama, N. H., Watabe, A. M., Carlisle, H. J., Porter, K., Charlesworth, P., Monti, J., Strathdee, D. J. C., O'Carroll, C. M., Martin, S. J., Morris, R. G. M., O'Dell, T. J., & Grant, S. G. N. (2002). SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor. The Journal of Neuroscience, 22, 9721–9732.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Korzus, E., Rosenfeld, M. G., & Mayford, M. (2004). CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron, 42, 961–972.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lauterborn, J. C., Palmer, L. C., Jia, Y., Pham, D. T., Hou, B., Wang, W., Trieu, B. H., Cox, C. D., Kantorovich, S., Gall, C. M., & Lynch, G. (2016). Chronic ampakine treatments stimulate dendritic growth and promote learning in middle-aged rats. The Journal of Neuroscience, 36, 1636–1646.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee, A. M., Kanter, B. R., Wang, D., Lim, J. P., Zou, M. E., Qiu, C., McMahon, T., Dadgar, J., Fischbach-Weiss, S. C., & Messing, R. O. (2013). Pkrcz null mice show normal learning and memory. Nature, 493, 416–419.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ling, D. S., Benardo, L. S., Serrano, P. A., Blace, N., Kelly, M. T., Crary, J. F., & Sacktor, T. C. (2002). Protein kinase Mζ is necessary and sufficient for LTP maintenance. Nature Neuroscience, 5, 295–296.

    CAS  PubMed  Google Scholar 

  • Liu, J., Fukunaga, K., Yamamoto, H., Nishi, K., & Miyamoto, E. (1999). Differential roles of Ca2+/calmodulin-dependent protein kinase II and mitogen-activated protein kinase activation in hippocampal long-term potentiation. The Journal of Neuroscience, 19, 8292–8299.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu, R. Y., Zhang, Y., Smolen, P., Cleary, L. J., & Byrne, J. H. (2020). Role of p90 ribosomal S6 kinase in long-term synaptic facilitation and enhanced neuronal excitability. Scientific Reports, 10, 608.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lynch, G., Cox, C. D., & Gall, C. M. (2014). Pharmacological enhancement of memory or cognition in normal subjects. Frontiers in Systems Neuroscience, 8, 90.

    PubMed  PubMed Central  Google Scholar 

  • Matsushita, M., Tomizawa, K., Moriwaki, A., Li, S. T., Terada, H., & Matsui, H. (2001). A high-efficiency protein transduction system demonstrating the role of PKA in long-lasting long-term potentiation. The Journal of Neuroscience, 21, 6000–6007.

    CAS  PubMed  PubMed Central  Google Scholar 

  • McBride, S. M. J., Choi, C. H., Wang, Y., Liebelt, D., Braunstein, E., et al. (2005). Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome. Neuron, 45, 753–764.

    CAS  PubMed  Google Scholar 

  • McManus, K. J., & Hendzel, M. J. (2001). CBP, a transcriptional coactivator and acetyltransferase. Biochemistry and Cell Biology, 79, 253–266.

    CAS  PubMed  Google Scholar 

  • Messaoudi, E., Ying, S. W., Kanhema, T., Croll, S. D., & Bramham, C. R. (2002). Brain-derived neurotrophic factor triggers transcription-dependent, late phase long-term potentiation in vivo. The Journal of Neuroscience, 22, 7453–7461.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morozov, A., Muzzio, I. A., Bourtchouladze, R., Van-Strien, N., Lapidus, K., Yin, D., Winder, D. G., Adams, J. P., & Sweatt, J. D. (2003). Rap1 couples cAMP signaling to a distinct pool of p42/p44MAPK regulating excitability, synaptic plasticity, learning and memory. Neuron, 39, 309–325.

    CAS  PubMed  Google Scholar 

  • Mozafari, N., Shamsizadeh, A., Fatemi, I., Allahtavakoli, M., Moghadam-Ahmadi, A., Kaviani, E., & Kaeidi, A. (2018). CX691, as an AMPA receptor positive modulator, improves the learning and memory in a rat model of Alzheimer’s disease. Iranian Journal of Basic Medical Sciences, 21, 724–730.

    PubMed  PubMed Central  Google Scholar 

  • Murakoshi, H., Shin, M. E., Parra-Bueno, P., Szatmari, E. M., Shibata, A. C. E., & Yasuda, R. (2017). Kinetics of endogenous CaMKII required for synaptic plasticity revealed by optogenetic kinase inhibitor. Neuron, 94, 37–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Murru, L., Vezzoli, E., Longatti, A., Ponzoni, L., Falgui, A., Folci, A., Moretto, E., Bianchi, V., Brajda, D., Sala, M., D’Adomo, P., Bassani, S., Francolini, M., & Passafaro, M. (2017). Pharmacological modulation of AMPAR rescues intellectual disability-like phenotype in Tm4sf2−/y mice. Cerebral Cortex, 27, 5369–5384.

    PubMed  PubMed Central  Google Scholar 

  • Niehof, M., Manns, M. P., & Trautwein, C. (1997). CREB controls LAP/C/EBP β transcription. Molecular and Cellular Biology, 17, 3600–3613.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Panja, D., & Bramham, C. R. (2014). BDNF mechanisms in late LTP formation: A synthesis and breakdown. Neuropharmacology, 76, 664–676.

    CAS  PubMed  Google Scholar 

  • Pastalkova, E., Serrano, P., Pinkhasova, D., Wallace, E., Fenton, A. A., & Sacktor, T. C. (2006). Storage of spatial information by the maintenance mechanism of LTP. Science, 313, 1141–1144.

    CAS  PubMed  Google Scholar 

  • Patterson, S. L., Pittenger, C., Morozov, A., Martin, K. C., Scanlin, H., Drake, C., & Kandel, E. R. (2001). Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron, 32, 123–140.

    CAS  PubMed  Google Scholar 

  • Pereira, P. M., Schneider, A., Pannetier, S., Heron, D., & Hanauer, A. (2010). Coffin-Lowry syndrome. European Journal of Human Genetics, 18, 627–633.

    PubMed  Google Scholar 

  • Peters, M., Bletsch, M., Stanley, J., Wheeler, D., Scott, R., & Tully, T. (2014). The PDE4 inhibitor HT-0712 improves hippocampus-dependent memory in aged mice. Neuropsychopharmacology, 39, 2938–2948.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Peterson, J. J., & Novick, S. J. (2007). Nonlinear blending: A useful general concept for the assessment of combination drug synergy. Journal of Receptor and Signal Transduction Research, 27, 125–146.

    CAS  PubMed  Google Scholar 

  • Petrij, F., Giles, R. H., Dauwerse, H. G., Saris, J. J., Hennekam, R. C., Masuno, M., Tommerup, N., van Ommen, G. J., Goodman, R. H., Peters, D. J., & Breuning, M. H. (1995). Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature, 376, 348–351.

    CAS  PubMed  Google Scholar 

  • Pettigrew, D. B., Smolen, P., Baxter, D. A., & Byrne, J. H. (2005). Dynamic properties of regulatory motifs associated with induction of three temporal domains of memory in Aplysia. Journal of Computational Neuroscience, 18, 163–181.

    PubMed  Google Scholar 

  • Pittenger, C., Huang, Y. Y., Paletzki, R. F., Bourtchouladze, R., Scanlin, H., Vronskaya, S., & Kandel, E. R. (2002). Reversible inhibition of CREB/ATF transcription factors in region CA1 of the dorsal hippocampus disrupts hippocampus-dependent spatial memory. Neuron, 34, 447–462.

    CAS  PubMed  Google Scholar 

  • Pologruto, T. A., Yasuda, R., & Svoboda, K. (2004). Monitoring neural activity and [Ca2+] with genetically encoded Ca2+ indicators. The Journal of Neuroscience, 24, 9572–9579.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Radin, D. P., Zhong, S., Purcell, R., & Lippa, A. (2016). Acute ampakine treatment ameliorates age-related deficits in long-term potentiation. Biomedicine & Pharmacotherapy, 84, 806–809.

    CAS  Google Scholar 

  • Rawashdeh, O., Jilg, A., Maronde, E., Fahrenkrug, J., & Stehle, J. H. (2016). Period1 gates the circadian modulation of memory-relevant signaling in mouse hippocampus by regulating the nuclear shuttling of the CREB kinase pp90RSK. Journal of Neurochemistry, 138, 731–745.

    CAS  PubMed  Google Scholar 

  • Qiu, Z., & Ghosh, A. (2008). A calcium-dependent switch in a CREST-BRG1 complex regulates activity-dependent gene expression. Neuron, 60, 775–787.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Roberson, E. D., & Sweatt, J. D. (1996). Transient activation of cyclic AMP-dependent protein kinse during hippocampal long-term potentiation. The Journal of Biological Chemistry, 271, 30436–30441.

    CAS  PubMed  Google Scholar 

  • Roelfsema, J. H., & Peters, D. J. (2007). Rubinstein-Taybi syndrome: Clinical and molecular overview. Expert Reviews in Molecular Medicine, 9, 1–16.

    PubMed  Google Scholar 

  • Ronan, J. L., Wu, W., & Crabtree, G. R. (2013). From neural development to cognition: Unexpected roles for chromatin. Nature Reviews. Genetics, 14, 347–359.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenblum, K., Futter, M., Voss, K., Erent, M., Skehel, P. A., French, P., Obosi, L., Jones, M. W., & Bliss, T. V. P. (2002). The role of extracellular regulated kinases I/II in late-phase long-term potentiation. The Journal of Neuroscience, 22, 5432–5441.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rossato, J. I., Gonzalez, M. C., Radiske, A., Apolinario, G., Conde-Ocazionez, S., Bevilaqua, L. R., & Cammarota, M. (2019). PKMζ inhibition disrupts reconsolidation and erases object recognition memory. The Journal of Neuroscience, 39, 1828–1841.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rubinstein, J. H., & Taybi, H. (1963). Broad thumbs and toes and facial abnormalities. A possible mental retardation syndrome. Am. J. Dis. Child, 105, 588–608.

    CAS  PubMed  Google Scholar 

  • Rusconi, D., Negri, G., Colapietro, P., Picinelli, C., Milani, D., Spena, S., Magnani, C., Silengo, M. C., Sorasio, L., Curtisova, V., Cavaliere, M. L., Prontera, P., Stangoni, G., Ferrero, G. B., Biamino, E., Fischetto, R., Piccione, M., Gasparini, P., Salviati, L., Selicrni, G., Finelli, P., Larizza, L., & Gervasini, C. (2015). Characterization of 14 novel deletions underlying Rubinstein-Taybi syndrome: An update of the CREBBP deletion repertoire. Human Genetics, 134, 613–626.

    CAS  PubMed  Google Scholar 

  • Schmitt, J. M., Guire, E. S., Saneyoshi, T., & Soderling, T. R. (2005). Calmodulin-dependent kinase kinase/calmodulin kinase I activity gates extracellular-regulated kinase-dependent long-term potentiation. The Journal of Neuroscience, 25, 1281–1290.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Seese, R. R., Le, A. A., Wang, K., Cox, C. D., Lynch, G., & Gall, C. M. (2019). A TrkB agonist and ampakine rescue synaptic plasticity and multiple forms of memory in a mouse model of intellectual disability. Neurobiol. Dis., 134, 104604. https://doi.org/10.1016/j.nbd.2019.104604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Severyn, B., Liehr, R. A., Wolicki, A., Nguyen, K. H., Hudak, E. M., Ferrer, M., Caldwell, J. S., Hermes, J. D., Li, J., & Tudor, M. (2011). Parsimonious discovery of synergistic drug combinations. ACS Chemical Biology, 6, 1391–1398.

    CAS  PubMed  Google Scholar 

  • Shors, T. J., Servatius, R. J., Thompson, R. F., Rogers, G., & Lynch, G. (1995). Enhanced glutamatergic neurotransmission facilitates classical conditioning in the freely-moving rat. Neuroscience Letters, 186, 153–156.

    CAS  PubMed  Google Scholar 

  • Shu, G., Kramar, E. A., Lopez, A. J., Huynh, G., Wood, M. A., & Kwapis, J. L. (2018). Deleting HDAC3 rescues long-term memory impairments induced by disruption of the neuron-specific chromatin remodeling subunit BAF53b. Learning & Memory, 25, 109–114.

  • Slinker, B. K. (1998). The statistics of synergism. Journal of Molecular and Cellular Cardiology, 30, 723–731.

    CAS  PubMed  Google Scholar 

  • Smolen, P., Baxter, D. A., & Byrne, J. H. (2006). A model of the roles of essential kinases in the induction and expression of late long-term potentiation. Biophysical Journal, 90, 2760–2775.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Smolen, P., Baxter, D. A., & Byrne, J. H. (2012). Molecular constraints on synaptic tagging and maintenance of long-term potentiation: A predictive model. PLoS Computational Biology, 8, e1002620.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Smolen, P., Baxter, D. A., & Byrne, J. H. (2014). Simulations suggest pharmacological methods for rescuing long-term potentiation. Journal of Theoretical Biology, 360, 243–250.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Song, Z. X., Chen, Q., Ding, Q., Zheng, F., Li, C. W., Xu, L. P., & Wang, H. B. (2015). Function of Ca2+/calmodulin-dependent protein kinase IV in Ca2+-stimulated neuronal signaling and behavior. Science China. Life Sciences, 58, 6–13.

    CAS  PubMed  Google Scholar 

  • Staahl, B. T., & Crabtree, G. R. (2013). Creating a neural specific chromatin landscape by npBAF and nBAF complexes. Current Opinion in Neurobiology, 23, 903–913.

    CAS  PubMed  Google Scholar 

  • Staubli, U., Rogers, G., & Lynch, G. (1994). Facilitation of glutamate receptors enhances memory. Proc. Natl. Acad. Sci. USA, 91, 777–781.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tao, X., Finkbeiner, S., Arnold, D. B., Shaywitz, A. J., & Greenberg, M. E. (1998). Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron, 20, 709–726.

    CAS  PubMed  Google Scholar 

  • Taubenfeld, S. M., Milekic, M. H., Monti, B., & Alberini, C. M. (2001). The consolidation of new but not reactivated memory requires hippocampal C/EBPβ. Nature Neuroscience, 4, 813–818.

    CAS  PubMed  Google Scholar 

  • Tian, M., Zeng, Y., Hu, Y., Yuan, X., Liu, S., Li, J., Lu, P., Sun, Y., Gao, L., Fu, D., Li, Y., Wang, S., & McClintock, S. M. (2015). 7, 8-dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome. Neuropharmacology, 89, 43–53.

    CAS  PubMed  Google Scholar 

  • Tsokas, P., Hsieh, C., Yao, Y., Lesburgueres, E., Wallace, E. J. C., et al. (2016). Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice. eLife, 5, e14846.

    PubMed  PubMed Central  Google Scholar 

  • Vecsey, C. G., Hawk, J. D., Lattal, K. M., Stein, J. M., Fabian, S. A., Attner, M. A., Cabrera, S. M., McDonough, C. B., Brindle, P. K., Abel, T., & Wood, M. A. (2007). Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. The Journal of Neuroscience, 27, 6128–6140.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vincent, P., & Brusciano, D. (2001). Cyclic AMP imaging in neurons in brain slice preparation. J. Neurosci. Method., 108, 189–198.

    CAS  Google Scholar 

  • Vogel-Ciernia, A., Matheos, D. P., Barrett, R. M., Kramar, E. A., Azzawi, S., Chen, Y., Magnan, C. N., Zeller, M., Sylvain, A., Haettig, J., Jia, Y., Tran, A., Dang, R., Post, R. J., Chabrier, M., Babayan, A. H., Wu, J. I., Crabtree, G. R., Baldi, P., Baram, T. Z., Lynch, G., & Wood, M. A. (2013). The neuron-specific chromatin regulatory subunit BAF53b is necessary for synaptic plasticity and memory. Nature Neuroscience, 16, 552–561.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vogel-Ciernia, A., & Wood, M. A. (2014). Neuron-specific chromatin remodeling: A missing link in epigenetic mechanisms underlying synaptic plasticity, memory, and intellectual disability disorders. Neuropharmacology, 80, 18–27.

    CAS  PubMed  Google Scholar 

  • Volk, L. J., Bachman, J. L., Johnson, R., Yu, Y., & Huganir, R. L. (2013). PKM-ζ is not required for hippocampal synaptic plasticity, learning and memory. Nature, 493, 420–423.

    CAS  PubMed  Google Scholar 

  • Waltereit, R., Dammermann, B., Wulff, P., Scafidi, J., Staubli, U., Kauselmann, G., Bundman, G., & Kuhl, D. (2001). Arg3.1/Arc mRNA induction by Ca2+ and cAMP requires protein kinase a and mitogen-activated protein kinase/extracellular regulated kinase activation. The Journal of Neuroscience, 21, 5484–5493.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, S., Sheng, T., Ren, S., Tian, T., & Lu, W. (2016). Distinct roles of PKCι/λ and PKMζ in the initiation and maintenance of hippocampal long-term potentiation and memory. Cell Reports, 16, 1954–1961.

    CAS  PubMed  Google Scholar 

  • White, A. O., Kramar, E. A., Lopez, A. J., Kwapis, J. L., Doan, J., Saldana, D., Davatolhagh, M. F., Alaghband, Y., Blurton-Jones, M., Matheos, D. P., & Wood, M. A. (2016). BDNF rescues BAF53b-dependent synaptic plasticity and cocaine-associated memory in the nucleus accumbens. Nature Communications, 7, 11725.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wong, S. T., Athos, J., Figueroa, X. A., Pineda, V. V., Schaefer, M. L., Chavkin, C. C., Muglia, L. J., & Storm, D. R. (1999). Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-dependent long-term memory and late phase LTP. Neuron, 23, 787–798.

    CAS  PubMed  Google Scholar 

  • Woo, N. H., Duffy, S. N., Abel, T., & Nguyen, P. V. (2000). Genetic and pharmacological demonstration of differential recruitment of cAMP-dependent protein kinase activation by synaptic activity. Journal of Neurophysiology, 84, 2739–2745.

    CAS  PubMed  Google Scholar 

  • Wood, M. A., Kaplan, M. P., Park, A., Blanchard, E. J., Oliveira, A. M., Lombardi, T. L., & Abel, T. (2005). Transgenic mice expressing a truncated form of CREB-binding protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage. Learning & Memory, 12, 111–119.

    Google Scholar 

  • Wu, G. Y., Deisseroth, K., & Tsien, R. W. (2001). Activity-dependent CREB phosphorylation: Convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Proc. Natl. Acad. Sci. USA, 98, 2808–2813.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu, J. I., Lessard, J., Olave, I. A., Qiu, Z., Ghosh, A., Graef, I. A., & Crabtree, G. R. (2007). Regulation of dendritic development by neuron-specific chromatin remodeling complexes. Neuron, 56, 94–108.

    CAS  PubMed  Google Scholar 

  • Xing, J., Ginty, D. D., & Greenberg, M. E. (1996). Coupling of the Ras-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science, 273, 959–963.

    CAS  PubMed  Google Scholar 

  • Xing, J., Kornhauser, J. M., Xia, Z., Thiele, E. A., & Greenberg, M. E. (1998). Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation. Molecular and Cellular Biology, 18, 1946–1955.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yan, K., Rousseau, J., Littlejohn, R. O., Kiss, C., Lehman, A., Rosenfeld, J. A., Stumpel, C. T. R., Stegmann, A. P. A., Robak, L., Scaglia, F., Nguyen, T. T. M., Fu, H., Ajeawung, N. F., Camurri, M. V., Li, L., Gardham, A., Panis, B., Almannai, M., Sacoto, M. J. G., Baskin, B., Ruivenkamp, C., Xia, F., Bi, W., DDD Study, CAUSES Study, Cho, M. T., Potjer, T. P., Santen, G. W. E., Parker, M. J., Canham, N., McKinnon, M., Potocki, L., MacKenzie, J., Roeder, E. R., Campeau, P. M., & Yang, X. J. (2017). Mutations in the chromatin regulator gene BRPF1 cause syndromic intellectual disability and deficient histone acetylation. American Journal of Human Genetics, 100, 91–104.

    CAS  PubMed  Google Scholar 

  • Yang, L., Mao, L., Tang, Q., Samdani, S., Liu, Z., & Wang, J. Q. (2004). A novel Ca2+−independent pathway to extracellular signal-regulated protein kinase by coactivation of NMDA receptors and metabotropic glutamate receptor 5 in neurons. The Journal of Neuroscience, 24, 10846–10857.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ying, S. W., Futter, M., Rosenblum, K., Webber, M. J., Hunt, S. P., Bliss, T. V., & Branham, C. R. (2002). Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: Requirement for ERK activation coupled to CREB and upregulation of arc synthesis. The Journal of Neuroscience, 22, 1532–1540.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yoo, M., Choi, K. Y., Kim, J., Kim, M., Shim, J., Choi, J. H., Cho, H. Y., Oh, J. P., Kim, H. S., Kaang, B. K., & Han, J. H. (2017). BAF53b, a neuron-specific nucleosome remodeling factor, is induced after learning and facilitates long-term memory consolidation. The Journal of Neuroscience, 37, 3686–3697.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zeng, Y., Wang, X., Wang, Q., Liu, S., Hu, X., & McClintock, S. M. (2013). Small molecules activating TrkB receptor for treating a variety of CNS disorders. CNS Neurol. Disord. Drug Targets, 12, 1066–1077.

    CAS  PubMed  Google Scholar 

  • Zhang, J. W., Klemm, D. J., Vinson, C., & Lane, M. D. (2004). Role of CREB in transcriptional regulation of CCAAT/enhancer binding protein β gene during adipogenesis. The Journal of Biological Chemistry, 279, 4471–4478.

    CAS  PubMed  Google Scholar 

  • Zhang, Y., Smolen, P., Baxter, D. A., & Byrne, J. H. (2014). Computational analyses of synergism in small molecular network motifs. PLoS Computational Biology, 10, e1003524.

    PubMed  PubMed Central  Google Scholar 

  • Zimmerman, G. R., Lehar, J., & Keith, C. T. (2007). Multi-target therapeutics: When the whole is greater than the sum of the parts. Drug Discovery Today, 12, 34–42.

    Google Scholar 

Download references

Acknowledgments

We thank Y. Zhang for comments on an earlier draft of the manuscript. Supported by NIH grants NS102490 (to JHB) and AG051807 and AG057558 (to MAW).

Author information

Authors and Affiliations

  1. Department of Neurobiology and Anatomy, W.M. Keck Center for the Neurobiology of Learning and Memory, McGovern Medical School of the University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

    Paul Smolen, Douglas A. Baxter & John H. Byrne

  2. Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, 92697, USA

    Marcelo A. Wood

Authors
  1. Paul Smolen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcelo A. Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Douglas A. Baxter
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John H. Byrne
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul Smolen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Action Editor: Upinder Singh Bhalla

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(TXT 20 kb)

ESM 2

(TXT 44 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Smolen, P., Wood, M.A., Baxter, D.A. et al. Modeling suggests combined-drug treatments for disorders impairing synaptic plasticity via shared signaling pathways. J Comput Neurosci 49, 37–56 (2021). https://doi.org/10.1007/s10827-020-00771-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10827-020-00771-4

Keywords

Search

Navigation