Review Article : Molecular and Cellular Mechanisms Underlying the Cognitive Deficits Associated With Neurofibromatosis 1

Abstract

Neurofibromatosis 1 is one of the most common single-gene disorders affecting neurologic function in humans. Mutations in the NF1 gene cause abnormalities in cell growth and differentiation and lead to a variety of learning disabilities. Neurofibromin has several biochemical functions, such as Ras-guanosine triphosphatase activity, adenylate cyclase modulation, and microtubule binding, all of which could be critical for brain function. We review how studies in mouse models are helping to unravel the molecular and cellular mechanisms underlying cognitive deficits in neurofibromatosis 1. These studies suggest that the learning disabilities associated with neurofibromatosis 1 are caused by excessive Ras activity that leads to increased γ-aminobutyric acid (GABA_A) inhibition and to decreased long-term potentiation. These findings have brought us closer than ever to the development of possible treatments for the learning disabilities associated with neurofibromatosis 1. (J Child Neurol 2002;17:622-626).

Get full access to this article

View all access options for this article.

References

Gutmann DH , Collins FS : von Recklinghausen neurofibromatosis, in Scriver CR , et al: The Metabolic and Molecular Basis of Inherited Disease, 7th ed, vol2. New York, McGraw-Hill, 1995, 14:1-19.

Huson SM , Hughes Rac : The Neurofibromatoses: A Pathogenic and Clinical Overview. London, Chapman & Hall, 1994 .

Viskochil D. : Neurofibromatosis 1. Am JMed Genet 1999;89:v-viii.

Friedman JM : Epidemiology of neurofibromatosis type 1. Am J Med Genet 1999;89:1-6.

Cichowski K. , Jacks T. : NF1 tumor suppressor gene function: Narrowing the GAP. Cell 2001;104:593-604.

North K. : Neurofibromatosis type 1. Am J Med Genet 2000 ;97: 119-127.

Ozonoff S. : Cognitive impairment in neurofibromatosis type 1. Am J Med Genet 1999;89:45-52.

Eliason MJ : Neurofibromatosis: Implications for learning and behavior. Dev Behav Pediatr 1986;7:175-179.

Eliason MJ : Neuropsychological patterns: Neurofibromatosis compared to developmental learning disorders. Neurofibromatosis 1988;1:17-25.

10.

Varnhagen C. , Lewin S. , Das JP , et al: Neurofibromatosis and psychological processes. J Dev Behav Pediatr 1988;9:257-265.

11.

Eldridge R. , Denckla MB , Bien E. , et al: Neurofibromatosis type 1 (Recklinghausen's disease). Neurologic and cognitive assessment with sibling controls. Am J Dis Child 1989; 143:833-837.

12.

North K. : Neurofibromatosis type 1: Review of the first 200 patients in an Australian clinic. J Child Neurol 1993;8:395-402.

13.

North K. , Joy P. , Yuille D. , et al: Cognitive function and academic performance in children with neurofibromatosis type 1. Dev Med Child Neurol 1995;37:427-436.

14.

Chapman CA , Waber DP , Bassett N. , et al: Neurobehavioral profiles of children with neurofibromatosis 1 referred for learning disabilities are sex-specific. Am J Med Genet 1996;67:127-132.

15.

Zoller ME , Rembeck B. , Backman L. : Neuropsychological deficits in adults with neurofibromatosis type 1. Acta Neurol Scand 1997; 95:225-232.

16.

North K. , Joy P. , Yuille D. , et al: Specific learning disability in children with neurofibromatosis type I: Significance of MRI abnormalities. Neurology 1994;44:878-883.

17.

Bernards A. , Snijders AJ , Hannigan GE , et al: Mouse neurofibromatosis type 1 cDNA sequence reveals high degree of conservation of both coding and noncoding mRNA segments. Hum Mol Genet 1993;2:645-650.

18.

Hajra A. , Martin-Gallardo A. , Tarle SA , et al: DNA sequences in the promoter region of the NF1 gene are highly conserved between human and mouse. Genomics 1994;21:649-652.

19.

Jacks T. , Shih TS , Schmitt EM , et al: Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet 1994;7: 353-361.

20.

Brannan CI , Perkins AS , Vogel KS , et al: Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues . Genes Dev 1994;8:1019-1029.

21.

Cichowski K. , Shih TS , Schmitt E. , et al: Mouse models of tumor development in neurofibromatosis type 1. Science 1999;286: 2172-2176.

22.

Vogel KS , Klesse J. , Velasco-Miguel S. : Mouse tumor model for neurofibromatosis type 1. Science 1999;286:2176-2179.

23.

Nordlund ML , Rizvi TA , Brannan CI , Ratner N. : Neurofibromin expression and astrogliosis in neurofibromatosis (type 1) brains. J Neuropathol Exp Neurol 1995;54:588-600.

24.

Rizvi TA , Akunuru S. , de Courten-Myers G. , et al: Region-specific astrogliosis in brains of mice heterozygous for mutations in the neurofibromatosis type 1 (Nfl) tumor suppressor. Brain Res 1999;816:111-123.

25.

Silva AJ , Frankland PW , Marowitz Z. , et al: A mouse model for the learning and memory deficits associated with neurofibromatosis type I. Nat Genet 1997 ;15:281-284.

26.

Frankland PW , Cestari V. , Filipkowski R. , et al: The dorsal hippocampus is essential for context discrimination but not for contextual conditioning. Behav Neurosci 1998;112:863-874.

27.

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 1993;53:305-313.

28.

Costa RM , Elgersma Y. , Silva AJ : Modeling cognitive disorders: From genes to therapies, in Fisch G (ed): Genetics and Genomics of NeurobehavioraL Disorders. Totowa, NJ, Humana Press , 2002, in press.

29.

Denckla MB , Hofman K. , Mazzocco MM , et al: Relationship between T2-weighted hyperintensities (unidentified bright objects) and lower IQs in children with neurofibromatosis-1. Am J Med Genet 1996;67:98-102.

30.

Hofman KJ , Harris EL , Bryan RN , Denckla MB : Neurofibromatosis type 1: The cognitive phenotype. J Pediatr 1994;124(Suppl): S1-S8.

31.

Duffner PK , Cohen ME , Seidel FG , Shucard DW : The significance of MRI abnormalities in children with neurofibromatosis. Neurology 1989;39:373-378.

32.

Ferner RE , Chaudhuri R. , Bingham J. , et al: MRI in neurofibromatosis 1. The nature and evolution of increased intensity T2 weighted lesions and their relationship to intellectual impairment . J Neurol Neurosurg Psychiatry 1993;56:492-495.

33.

Legius E. , Descheemaeker MJ , Steyaert J. , et al: Neurofibromatosis type 1 in childhood: Correlation of MRI findings with intelligence. J Neurol Neurosurg Psychiatry 1995;59:638-640.

34.

Costa RM , Yang T. , Huynh DP , et al: Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1. Nat Genet 2001;27:399-405.

35.

Anderson LB , Pulst SM , Viscochil D. : A conserved alternative splice in the von Recklinghausen neurofibromatosis (NF1) gene produces two neurofibromin isoforms, both of which have GTPase-activating protein activity. Mol Cell Biol 1993; 13:487-495.

36.

Viskochil DH : Gene structure and function in Upadhyaya M , Cooper DN (eds): Neurofibromatosis Type I: From Genotype to Phenotype. Oxford, BIOS Scientific Publishers Limited, 1998, 39-56.

37.

Zhu Y. , Romero MI , Ghosh P. , et al: Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes Dev 2001;15:859-876.

38.

Martin GA , Viskochil D. , Bollag G. , et al: The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 1990;63:843-849.

39.

Xu GF , Lin B. , Tanaka K. , et al: The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 1990;63:835-841.

40.

Ballester R. , Marchuk D. , Boguski M. , et al: The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 1990;63:851-859.

41.

Guo HF , The I. , Hannan F. , et al: Requirement of Drosophila NF1 for activation of adenylyl cyclase by PACAP38-like neuropeptides. Science 1997 ;276:795-798.

42.

Guo HF , Tong J. , Hannan F. , et al: A neurofibromatosis-1-regulated pathway is required for learning in Drosophila. Nature 2000; 403:895-898.

43.

Xu H. , Gutmann DH : Mutations in the GAP-related domain impair the ability of neurofibromin to associate with microtubules. Brain Res 1997 ;759:149-152.

44.

Tong J. , Hannan F. , Zhu Y. , et al: Neurofibromin regulates G protein-stimulated adenylyl cyclase activity . Nat Neurosci 2002;14:14.

45.

Ingram DA , Hiatt K. , King AJ , et al: Hyperactivation of p21 (ras) and the hematopoietic-specific Rho GTPase, Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro. J Exp Med 2001;194:57-69.

46.

Williams JA , Su HS , Bernards A. , et al: A circadian output in Drosophila mediated by neurofibromatosis-1 and Ras/MAPK. Science 2001;293:2251-2256.

47.

Klose A. , Ahmadian MR , Schuelke M. , et al: Selective disactivation of neurofibromin GAP activity in neurofibromatosis type 1. Hum Mol Genet 1998;7:1261-1268.

48.

Costa RM , Federov NB , Kogan JH , et al: Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 2002;415:526-530.

49.

Ohno M. , Frankland PW , Chen AP , et al: Inducible, pharmacogenetic approaches to the study of learning and memory. Nat Neurosci 2001;4:1238-1243.

50.

Brambilla R. , Gnesutta N. , Minichiello L. , et al: A role for the Ras signalling pathway in synaptic transmission and long-term memory. Nature 1997;390:281-286.

51.

Atkins CM , Selcher JC , Petraitis J. , et al: The MAPK cascade is required for mammalian associative learning . Nat Neurosci 1998; 1:602-609.

52.

Giese KP , Friedman E. , Telliez JB , et al: Hippocampus-dependent learning and memory is impaired in mice lacking the Ras-guanine-nucleotide releasing factor 1 (Ras-GRF1). Neuropharmacology 2001;41:791-800.

53.

Minichiello L. , Korte M. , Wolfer D. , et al: Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 1999 ;24: 401-414.

54.

Chen AP , Ohno M. , Giese KP , et al: B-Raf kinase is critical for hippocampal ERK activation, long term potentiation and learning and memory. Submitted (2002).

55.

Lin CH , Yeh SH , Lin CH , et al: A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. Neuron 2001;31:841-851.

56.

Abbott LF , Nelson SB : Synaptic plasticity: Taming the beast. Nat Neurosci 2000;3(Suppl): 1178-1183.

57.

Bliss Tvp , Collingridge GL : A synaptic model of memory: Long-term potentiation in the hippocampus. Nature 1993;361:31-39.

58.

Malenka R. , Nicoll RA : Long-term potentiation―A decade of progress? Science 1999;285:1870-1874.

59.

Morris Rgm , Garrud P. , Rawlins Jnp , O'Keefe J. : Place navigation impaired in rats with hippocampal lesions. Nature 1982;297: 681-683.

60.

Cho YH , Friedman E. , Silva AJ : Ibotenate lesions of the hippocampus impair spatial learning but not contextual fear conditioning in mice. Behav Brain Res 1999;98:77-87.

61.

Scoville WB , Milner B. : Loss of recent memory after hippocampal bilateral lesions. JNeurol Neurosurg Psychiatry 1957 ;20: 11-12.

62.

Zola-Morgan S. , Squire LR : Neuroanatomy of memory. Annu Rev Neurosci 1993;16:547-563.

63.

Larson J. , Wong D. , Lynch G. : Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation. Brain Res 1986;368:347-350.

64.

Chorvatova A. , Gendron L. , Bilodeau L. , et al: A Ras-dependent chloride current activated by adrenocorticotropin in rat adrenal zona glomerulosa cells. Endocrinology 2000;141:684-692.

65.

Manabe T. , Aiba A. , Yamada A. , et al: Regulation of long-term potentiation by H-Ras through NMDA receptor phosphorylation. J Neurosci 2000;20:2504-2511.

66.

Grant SG , O'Dell TJ: Multiprotein complex signaling and the plasticity problem. Curr Opin Neurobiol 2001;11:363-368.

67.

Husi H. , Ward MA , Choudhary JS , et al: Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat Neurosci 2000;3:661-669.

68.

Brioni JD , Decker MW , Gamboa LP , et al: Muscimol injections in the medial septum impair spatial learning . Brain Res 1990;522: 227-234.

69.

Fujii S. , Jia Y. , Yang A. , Sumikawa K. : Nicotine reverses GABAergic inhibition of long-term potentiation induction in the hippocampal CA1 region. Brain Res 2000 ;863:259-265.

70.

Lu YM , Mansuy IM , Kandel ER , Roder J. : Calcineurin-mediated LTD of GABAergic inhibition underlies the increased excitability of CA1 neurons associated with LTP. Neuron 2000;26:197-205.

71.

Gusev PA , Alkon DL : Intracellular correlates of spatial memory acquisition in hippocampal slices: Long-term disinhibition of CA1 pyramidal cells. J Neurophysiol 2001;86:881-899.

72.

Paulsen O. , Moser EI : A model of hippocampal memory encoding and retrieval: GABAergic control of synaptic plasticity. Trends Neurosci 1998;21:273-278.

73.

Csicsvari J. , Hirase H. , Czurko A. , et al: Oscillatory coupling of hippocampal pyramidal cells and interneurons in the behaving rat. J Neurosci 1999;19:274-287.