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A mouse model for the learning and memory deficits associated with neurofibromatosis type I

A Corrigendum to this article was published on 01 August 2002


Neurofibromatosis type I (NF1) is one of the most commonly inherited neurological disorders in humans, affecting approximately one in 4,000 individuals1–3. NF1 results in a complex cluster of developmental and tumour syndromes that include benign neurofibromas, hyperpigmentation of melanocytes and hamartomas of the iris. Some NF1 patients may also show neurologic lesions, such as optic pathway gliomas, dural ectasia and aqueduct stenosis1–3. Importantly, learning disabilities occur in 30% to 45% of patients with NF1, even in the absence of any apparent neural pathology. The learning disabilities may include a depression in mean IQ scores, visuoperceptual problems and impairments in spatial cognitive abilities4–9. Spatial learning has been assessed with a variety of cognitive tasks and the most consistent spatial learning deficits have been observed with the Judgement of Line Orientation test4,7,10,11. It is important to note that some of these deficits could be secondary to developmental abnormalities1 and other neurological problems, such as poor motor coordination and attentional deficits9. Previous studies have suggested a role for neurofibromin in brain function. First, the expression of the Nf1 gene is largely restricted to neuronal tissues in the adult12,14. Second, this GTPase activating protein may act as a negative regulator of neurotrophin-mediated signalling15. Third, immunohistochemical studies suggest that activation of astrocytes may be common in the brain of NF1 patients13. Here, we show that the Nf1+/− mutation also affects learning and memory in mice. As in humans, the learning and memory deficits of the Nf1+/− mice are restricted to specific types of learning, they are not fully penetrant, they can be compensated for with extended training, and they do not involve deficits in simple associative learning.

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  1. 1

    Gutmann, D.H. & Collins, F.S. Recent progress towards understanding the molecular biology of von Recklinghausen neurofibromatosis. Annl. Neurol. 31, 555–561 (1992).

    CAS  Article  Google Scholar 

  2. 2

    Huson, S.M. & Hughes, R.A.C. The Neurofibromatoses: A Pathogenic and Clinical Overview, 204–252 (Chapman & Hall, London, 1994).

  3. 3

    Riccardi, V.M. Neurofibromatosis: Phenotype, Natural History and Pathogenesis, 195–213 (The Johns Hopkins Press Ltd., Baltimore, 1992).

    Google Scholar 

  4. 4

    Eliason, M.J. Neurofibromatosis: implications for learning and behavior. Dev. Behav. Pediatr. 7, 175–179 (1986).

    CAS  Article  Google Scholar 

  5. 5

    Eliason, M.J. Neuropsychological patterns: neurofibromatosis compared to developmental learning disorders. Neurofibromatosis 1, 17–25 (1988).

    CAS  PubMed  Google Scholar 

  6. 6

    Varnhagen, C. et al. Neurofibromatosis and psychological processes. Dev. Behav. Pediatr. 9, 257–265 (1988).

    CAS  Article  Google Scholar 

  7. 7

    Eldridge, R. et al. Neurofibromatosis type 1 (Recklinghausen's Disease): Neurologic and cognitive assessment with sibling controls. Am. J. Dis. Child 143, 833–837 (1989).

    CAS  Article  Google Scholar 

  8. 8

    North, K. Neurofibromatosis type 1: review of the first 200 patients in an Australian clinic. J. Child Neurol. 8, 395–402 (1993).

    CAS  Article  Google Scholar 

  9. 9

    North, K. Joy, P. Yuille, D. Cocks, N. & Hutchins, P. Cognitive function and academic performance in children with neurofibromatosis type 1. Dev. Med. Child. Neurol. 37, 427–436 (1995).

    CAS  Article  Google Scholar 

  10. 10

    Hofman, K.J. Harris, E.L. Bryan, R.N. & Denckla, M.B. Neurofibromatosis type 1: the cognitive phenotype. J. Pediatr. 124, 1–8 (1994).

    Article  Google Scholar 

  11. 11

    Joy, P. Roberts, C. North, K. & de Silva, M. Neuropsychological function and MRI abnormalities in neurofibromatosis type 1. Dev. Med. Child. Neurol. 37, 906–914 (1995).

    CAS  Article  Google Scholar 

  12. 12

    Datson, M.M. et al. The protein product of the neurofibromatsis type 1 gene is expressed at highest abundance in neurons, schwann cells, and oligodendrocytes. Neuron 8, 415–428 (1992).

    Article  Google Scholar 

  13. 13

    Nordlund, M.L. Rizvi, T.A. Brannan, C.I. & Ratner, N. Neurofibromin expression and astrogliosis in neurofibromatosis (type 1) brains. J. Neuropathol. Exp. Neurol. 54, 588–600 (1995).

    CAS  Article  Google Scholar 

  14. 14

    Nordlund, M. Gu, X. Shipley, M.T. & Ratner, N. Neurofibromin is enriched in the endoplasmic reticulum of CNS neurons. J. Neurosci. 13, 1588–1600 (1993).

    CAS  Article  Google Scholar 

  15. 15

    Vogel, K.S. Brannan, C.I. Jenkins, N.A. Copeland, N.G. & Parada, L.F. Loss of neurofibromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons. Cell 82, 733–742 (1995).

    CAS  Article  Google Scholar 

  16. 16

    Jacks, T. et al. Tumour predisposition in mice heterozygous for a targeted mutation of NF1. Nature Genet. 7, 353–361 (1994).

    CAS  Article  Google Scholar 

  17. 17

    Morris, R.G.M. Garrud, P. Rawlins, J.N.P. & O'Keefe, J. Place navigation impaired in rats with hippocampal lesions. Nature 297, 681–683 (1982).

    CAS  Article  Google Scholar 

  18. 18

    Sutherland, R.J. Kolb, B. & Whishaw, I.Q. Spatial mapping: definitive disruption by hippocampal or medial frontal cortical damage in the rat. Neurosci. Lett. 31, 271–276 (1982).

    CAS  Article  Google Scholar 

  19. 19

    Wu, Z.L. et al. Altered behavior and long-term potentiation in type I adenylyl cyclase mutant mice. Proc. Natl. Acad. Sci. USA 92, 220–224 (1995).

    CAS  Article  Google Scholar 

  20. 20

    Brandeis, R. Brandys, Y. & Yehuda, S. The use of the Morris Water Maze in the study of memory and learning. Intern. J. Neurosci. 48, 29–69 (1989).

    CAS  Article  Google Scholar 

  21. 21

    Crawley, J.N. Exploratory behavior models of anxiety in mice. Neurosci. Biobehav. Rev. 9, 37–44 (1985).

    CAS  Article  Google Scholar 

  22. 22

    Easton, D. Ponder, M. Huson, S. & Ponder, B. An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am. J. Hum. Genet. 53, 305–313 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Li, Y. Erzurumlu, R.S. Chen, C. Jhaveri, S. & Tonegawa, S. Whisker-related neuronal patterns fail to develop in the trigeminal brainstem nuclei of Nmdarf knockout mice. Cell 76, 427–437 (1994).

    CAS  Article  Google Scholar 

  24. 24

    Morris, R.G.M. Ahderson, E. Lynch, G.S. & Baudry, M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-asparate receptor antagonist, APS. Nature 319, 774–776(1986).

    CAS  Article  Google Scholar 

  25. 25

    Bliss, T.V.P. & Collingridge, G.L. A synaptic model of memory: Long-term-potentiation. Nature 361, 31–39 (1993).

    CAS  Article  Google Scholar 

  26. 26

    Kirn, J.J. & Fanselow, M.S. Modality-specific retrograde amnesia of fear. Science 256, 675–677 (1992).

    Article  Google Scholar 

  27. 27

    Phillips, R.G. & LeDoux, J.E. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274–285 (1992).

    CAS  Article  Google Scholar 

  28. 28

    Bourtchuladze, R. et al. Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element binding protein. Cell 79, 59–68 (1994).

    CAS  Article  Google Scholar 

  29. 29

    LeDoux, J.E. Clues from the brain. Annu. Rev. Psychol. 46, 209–235 (1995).

    CAS  Article  Google Scholar 

  30. 30

    Zhong, Y. Mediation of PACAP-like neuropeptide transmission by coactivation of Ras/Raf and cAMP signal transduction pathways in Drosophila. Nature 375, 588–592 (1995).

    CAS  Article  Google Scholar 

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Silva, A., Frankland, P., Marowitz, Z. et al. A mouse model for the learning and memory deficits associated with neurofibromatosis type I. Nat Genet 15, 281–284 (1997).

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