intellectual disabilities


learning

Specific intellectual disabilities are the most common neurological complication of children with Neurofibromatosis type I (NF1) and Noonan Syndrome (NS). The inherent complexity of these cognitive deficits, and the complications of pursuing their study in patients, motivated us to study them in mice.

We have shown that these mice have very specific learning deficits that have striking similarities to the deficits in individuals with NF1 and NS.

Our biological studies of mice with NF1 and NS have yielded not only the mechanism for the learning deficits in these two disorders, but also a treatment . Studies in patients have suggested that there are similar deficits in patients to the ones we identified in mice, and therefore, it is possible that the treatments we developed may be effective in patients.

Currently, there is a large clinical trial involving multiple clinical centers around the world testing the efficacy of the treatment we developed for cognitive deficits associated with NF1.

Our studies of NF1 demonstrated that this GAP modulates GABA release during learning and that this in turn controls long term changes in synaptic function and consequently learning and memory. NF1 results in increases in inhibition that lead to deficits in plasticity and learning. In contrast, NS causes increases in basal excitatory synaptic transmission that occlude long term changes in synaptic function, and consequently cause deficits in learning and memory.

2013 general talk about NF1

Key Publications:

Rachel K. Jonas, EunJi Roh, Caroline A. Montojo, Laura A. Pacheco, Tena Rosser, Alcino J. Silva, Carrie E. Bearden. Risky Decision Making in Neurofibromatosis Type 1: An Exploratory Study. Biological Psychiatry (in press)

Petrella, L.I., Y. Cai, J.V. Sereno, S.I. Goncalves, A.J. Silva, and M. Castelo-Branco, Brain and behaviour phenotyping of a mouse model of neurofibromatosis type-1: an MRI/DTI study on social cognition. Genes Brain Behav, 2016.

Bearden, C.E., G.S. Hellemann, T. Rosser, C. Montojo, R. Jonas, N. Enrique, L. Pacheco, S.A. Hussain, J.Y. Wu, J.S. Ho, J.J. McGough, C.A. Sugar, and A.J. Silva, A randomized placebo-controlled lovastatin trial for neurobehavioral function in neurofibromatosis I. Ann Clin Transl Neurol, 2016. 3(4): p. 266-79.(
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Tomson SN, Schreiner MJ, Narayan M, Rosser T, Enrique N, Silva AJ, Allen GI, Bookheimer SY, Bearden CE.Resting state functional MRI reveals abnormal network connectivity in neurofibromatosis 1. Hum Brain Mapp. 2015 Aug 25.PMID: 26304096

Korf B, Ahmadian R, Allanson J, Aoki Y, Bakker A, Wright EB, Denger B, Elgersma Y, Gelb BD, Gripp KW, Kerr B, Kontaridis M, Lazaro C, Linardic C, Lozano R, MacRae CA, Messiaen L, Mulero-Navarro S, Neel B, Plotkin S, Rauen KA, Roberts A, Silva AJ, Sittampalam SG, Zhang C, Schoyer L. The third international meeting on genetic disorders in the RAS/MAPK pathway: Towards a therapeutic approach. Am J Med Genet A. 2015

Omrani A, van der Vaart T, Mientjes E, van Woerden GM, Hojjati MR, Li KW, Gutmann DH, Levelt CN, Smit AB, Silva AJ, Kushner SA, Elgersma Y. HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1. Mol Psychiatry. 2015; PMID: 25917366

Lee, Y-S, Ehninger, D, Zhou, M, Oh, J-Y, Butz, D, Araki, T, Nam, CI, Balaji, J, Sano, Y, Amin, A, Kim, H, Burger, C, Neel, BG, and Silva, AJ. Mechanism and treatment for the learning and memory deficits associated with mouse models of Noonan syndrome, Nature Neuroscience 17, 1736–1743 (2014); PMID: 25383899 (PDF) ) For a News and Views on this article, click here

Shilyansky C, Karlsgodt KH, Cummings DM, Sidiropoulou K, Hardt M, James AS, Ehninger D, Bearden CE, Poirazi P, Jentsch JD, Cannon TD, Levine MS, Silva AJ. Neurofibromin regulates corticostriatal inhibitory networks during working memory performance. Proc Natl Acad Sci U S A. 2010 Jul 12. PMID: 20624961 (
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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)

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. (
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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.(PDF)

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