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  TSC work
Learning disabilities: the NF1 story Mouse model of NF1 Specific learning disabilities are the most common neurological complication of children with Neurofibromatosis type I (NF1). The inherent complexity of these cognitive deficits, and the complications of pursuing their study in patients, motivated us to study them in mice with the same mutation that in humans causes NF1(Nf1+/- mutants).  We have showed that these mice have very specific learning deficits that have striking similarities to the deficits of children with NF1.  Our biological studies of mice with NF1 have yielded a treatment for the learning deficits in mice, and we already have evidence that the same approach may ameliorate at least some of the cognitive deficits of patients with NF1. Molecular and cellular mechanism of learning disabilities associated with NF1 Our work showed that Nf1+/- mutants have spatial learning deficits, but not visible-platform deficits, in the Morris water maze.  Interestingly, we have recently found that although mice with a heterozygous null mutation of the K-ras gene (K-ras+/-) also showed spatial learning deficits, the K-ras+/- mutation can rescue the spatial learning phenotype of the Nf1+/- mice. Similarly, our work also shows that either the N-ras heterozygous null mutation (N-ras+/-) or a drug that decreases Ras function (FTI or farnesyl transferase inhibitor) can also reverse the learning deficits of the Nf1+/- mutants. These results suggest that increased Ras signaling is the cause for the learning deficits in Nf1+/- mutants. After demonstrating that the Nf1+/- mutation affects hippocampal-dependent spatial learning, we searched for the hippocampal physiological deficits underlying the hippocampal-dependent learning abnormalities of Nf1+/- mutants. Our studies of Nf1+/- mice revealed clear deficits in long-term potentiation ( LTP; 50% reduction). LTP is a mechanism thought to be involved in learning and memory.  Unlike LTP, other aspects of hippocampal physiology were unaffected by the Nf1+/- mutation (paired-pulse facilitation, augmentation, synaptic depression, recovery from synaptic depression, probability of release measured with the MK801 method, input resistance, single-cell firing thresholds, reversal of LTP, etc.). Our studies have also uncovered the cause for the LTP deficits: We discovered increased GABA-mediated inhibition in these mice. Remarkably, decreasing Ras function not only rescues the learning deficits of the Nf1+/- mutants, it also rescues their increase in GABA-inhibition and the decrease in LTP. Thus, our studies indicate that the Nf1 mutation leads to increased Ras function, that this leads to increased inhibition and that the increased inhibition results in the LTP deficits that underlie their learning impairments. Developing treatments for NF1 Recently, we have been able to take advantage of these findings to develop a treatment for NF1 in mice. We found that brief treatment with Lovastatin can reverse the biochemical, electrophysiological, and behavioral deficits of adult NF1 mutant mice. Currently, we are determining whether the same treatment is effective in patients. Initial findings are promising but inconclusive since we found that statin treatment improves some forms of cognitive function but perhaps not others (PDF). I beleive that longer trials with more subjects will be able to give us a definitive answer. These trials are currently under way.
The work described above was partially funded by NIH, but it could not have been possible without the generous help from the foundations listed below
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) 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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