Projects: Aging and Cognition CaMKII and learning Cognitive enhancements Cortical memories Enhancing plasticity and recovery Learning disabilities Memory allocation Novel memory genes Schizophrenia Science of Science Our NF1 work Our  TSC work	Neurodevelopmental disorders: reversing learning disabilities in adults Learning disabilities and other neurodevelopmental disorders affect more than 1 in 5 people world-wide, but to date there are very few treatments. To uncover the causes and develop treatments for learning disabilities, we started by studying single gene inherited conditions associated with learning disabilities and mental retardation, including Neurofibromatosis type I, Fragile X, Tuberous Sclerosis, and Noonan's Syndrome. Our studies have led us to new mechanisms of learning and memory, and to clinical trials to test treatments we developed based on these mechanisms. These and other recent animal model studies of neurodevelopmental disorders demonstrate that reversing the underlying molecular deficits can result in dramatic improvements in cognitive function even if treatments are started in adulthood. These findings mark a paradigmatic change in the way we understand and envision treating neurodevelopmental disorders. They raise the possibility that adult treatments could one day help the many millions of people affected with these disorders.
Key references Cui, Y, Costa, RM, Murphy, GG, Elgersma, Y, Zhu, Y, Gutmann, DH, Parada, LF, Mody, I, and Silva, AJ, Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell 2008 135(3) pp. 549 – 560. (PDF) Ehninger, D., Li, W, Fox, K, Stryker, MP, and Silva, AJ. Reversing neurodevelopmental disorders in adults. Neuron 2008;60(6):950-60..(PDF) Krab, L.C., A. de Goede-Bolder, F.K. Aarsen, S.M. Pluijm, M.J. Bouman, J.N. van der Geest, M. Lequin, C.E. Catsman, W.F. Arts, S.A. Kushner, A.J. Silva, C.I. de Zeeuw, H.A. Moll, and Y. Elgersma, Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. Jama, 2008. 300(3): p. 287-94.  (PDF) Ehninger, D., S. Han, C. Shilyansky, Y. Zhou, W. Li, D.J. Kwiatkowski, V. Ramesh, and A.J. Silva, Reversal of learning deficits in a Tsc2(+/-) mouse model of tuberous sclerosis. Nat Med, 2008.(Click Here) Chen, A.P., M. Ohno, K.P. Giese, R. Kuhn, R.L. Chen, and A.J. Silva, Forebrain-specific knockout of B-raf kinase leads to deficits in hippocampal long-term potentiation, learning, and memory. J Neurosci Res, 2006. 83(1): p. 28-38.(PDF). Kushner, S.A., Y. Elgersma, G.G. Murphy, D. Jaarsma, G.M. van Woerden, M.R. Hojjati, Y. Cui, J.C. LeBoutillier, D.F. Marrone, E.S. Choi, C.I. De Zeeuw, T.L. Petit, L. Pozzo-Miller, and A.J. Silva, Modulation of presynaptic plasticity and learning by the H-ras/extracellular signal-regulated kinase/synapsin I signaling pathway. J Neurosci, 2005. 25(42): p. 9721-34. (PDF) Li, W., Y. Cui, S.A. Kushner, R.A. Brown, J.D. Jentsch, P.W. Frankland, T.D. Cannon, and A.J. Silva, The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol, 2005. 15(21): p. 1961-7. (PDF) Frankland, P.W., Y. Wang, B. Rosner, T. Shimizu, B.W. Balleine, E.M. Dykens, E.M. Ornitz, and A.J. Silva, Sensorimotor gating abnormalities in young males with Fragile X syndrome and Fmr1-knockout mice. Molecular Psychiatry, 2004, 9, 417-425.(PDF) Dhaka, A., R. Costa, H. Hu, D. Irvin, A. Patel, H. Kornblum, A. Silva, T. O'Dell, and J. Colicelli, The Ras Effector Rin1 Modulates the Formation of Aversive Memories. Journal of Neuroscience, 2003,  23(3):748-57. Costa, R.M., N.B. Federov, J.H. Kogan, G.G. Murphy, J. Stern, M. Ohno, R. Kucherlapati, T. Jacks, and A.J. Silva, Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature, 2002. 415(6871): p. 526-30.(PDF) Ohno, M., P.W. Frankland, A.P. Chen, R.M. Costa, and A.J. Silva, Inducible, pharmacogenetic approaches to the study of learning and memory. Nature Neuroscience, 4, 1238-43, 2001.(PDF) Giese, K., E. Friedman, J.-P. Telliez, N. Fedorov, W. Wines, L. Feig, and A.J. Silva, Hippocampus-dependent learning and memory is impaired in mice lacking the ras-guanine-nucleotide releasing factor 1(ras-GRF-1). Neuropharmacology, 2001. 41(16): p. 791-800.(PDF) Costa, R.M., T. Yang, D.P. Huynh, S.M. Pulst, D.H. Viskochil, A.J. Silva, and C.I. Brannan, Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1. [Comment In: Nat Genet. 2001 Apr;27(4):354-5 UI: 21175732]. Nature Genetics, 2001. 27(4): p. 399-405.(PDF) Silva, A.J., P.W. Frankland, Z. Marowitz, E. Friedman, G. Lazlo, D. Cioffi, T. Jacks, and R. Bourtchuladze, A mouse model for the learning and memory deficits associated with neurofibromatosis type I. Nat Genet, 1997. 15(3): p. 281-4. Krab, L.C., A. de Goede-Bolder, F.K. Aarsen, S.M. Pluijm, M.J. Bouman, J.N. van der Geest, M. Lequin, C.E. Catsman, W.F. Arts, S.A. Kushner, A.J. Silva, C.I. de Zeeuw, H.A. Moll, and Y. Elgersma, Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. Jama, 2008. 300(3): p. 287-94.  (PDF) Ehninger, D., S. Han, C. Shilyansky, Y. Zhou, W. Li, D.J. Kwiatkowski, V. Ramesh, and A.J. Silva, Reversal of learning deficits in a Tsc2(+/-) mouse model of tuberous sclerosis. Nat Med, 2008.(Click Here) Chen, A.P., M. Ohno, K.P. Giese, R. Kuhn, R.L. Chen, and A.J. Silva, Forebrain-specific knockout of B-raf kinase leads to deficits in hippocampal long-term potentiation, learning, and memory. J Neurosci Res, 2006. 83(1): p. 28-38.(PDF). Kushner, S.A., Y. Elgersma, G.G. Murphy, D. Jaarsma, G.M. van Woerden, M.R. Hojjati, Y. Cui, J.C. LeBoutillier, D.F. Marrone, E.S. Choi, C.I. De Zeeuw, T.L. Petit, L. Pozzo-Miller, and A.J. Silva, Modulation of presynaptic plasticity and learning by the H-ras/extracellular signal-regulated kinase/synapsin I signaling pathway. J Neurosci, 2005. 25(42): p. 9721-34. (PDF) Li, W., Y. Cui, S.A. Kushner, R.A. Brown, J.D. Jentsch, P.W. Frankland, T.D. Cannon, and A.J. Silva, The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1. Curr Biol, 2005. 15(21): p. 1961-7. (PDF) Dhaka, A., R. Costa, H. Hu, D. Irvin, A. Patel, H. Kornblum, A. Silva, T. O'Dell, and J. Colicelli, The Ras Effector Rin1 Modulates the Formation of Aversive Memories. Journal of Neuroscience, 2003,  23(3):748-57. Costa, R.M., N.B. Federov, J.H. Kogan, G.G. Murphy, J. Stern, M. Ohno, R. Kucherlapati, T. Jacks, and A.J. Silva, Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature, 2002. 415(6871): p. 526-30.(PDF) Ohno, M., P.W. Frankland, A.P. Chen, R.M. Costa, and A.J. Silva, Inducible, pharmacogenetic approaches to the study of learning and memory. Nature Neuroscience, 4, 1238-43, 2001.(PDF) Giese, K., E. Friedman, J.-P. Telliez, N. Fedorov, W. Wines, L. Feig, and A.J. Silva, Hippocampus-dependent learning and memory is impaired in mice lacking the ras-guanine-nucleotide releasing factor 1(ras-GRF-1). Neuropharmacology, 2001. 41(16): p. 791-800.(PDF) Costa, R.M., T. Yang, D.P. Huynh, S.M. Pulst, D.H. Viskochil, A.J. Silva, and C.I. Brannan, Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1. [Comment In: Nat Genet. 2001 Apr;27(4):354-5 UI: 21175732]. Nature Genetics, 2001. 27(4): p. 399-405.(PDF) Silva, A.J., P.W. Frankland, Z. Marowitz, E. Friedman, G. Lazlo, D. Cioffi, T. Jacks, and R. Bourtchuladze, A mouse model for the learning and memory deficits associated with neurofibromatosis type I. Nat Genet, 1997. 15(3): p. 281-4.
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