In this chapter, we have covered a topic of pronounced importance—disorders of human cognition, specifically related to memory formation. We saw three examples of convergence of basic memory research with clinical investigation, highlighting neurofibromatosis mental retardation, Angelman Syndrome, and Fragile X mental retardation. It is quite striking how the detailed analysis of the basic signal transduction mechanisms underlying rodent learning and memory have converged upon many of the same molecular systems recently identified using human genetic characterization approaches in the study of mental retardation syndromes. I am cautiously optimistic that this convergence will ultimately lead to an improvement of the human condition, by identifying new therapeutic approaches to treating mental retardation.

On the abstract, intellectual side, the findings we have covered in this chapter also have interesting cognitive neurobio-logical implications. It appears that the last decades of parsing the esoteric details of synaptic plasticity and rodent memory mechanisms may well have lived up to its promise. In my opinion, it is not too early to begin to think of the types of mechanisms we have been covering in this book in the context of giving insights into human cognitive processing as well. The convergence of human and basic studies onto the same molecular cascades suggests that, indeed, we may be in the process of generating insights into the molecular basis of human cognition.

This line of thinking raises an interesting issue as well: the distinction between a developmental necessity for the gene products versus an acute, ongoing necessity as part of the signal transduction mechanisms subserving cognition. Many of the mutations we have discussed do not lead to gross morphological changes in the human CNS. Moreover, mouse studies, where available, indicate that baseline synaptic transmission is normal after loss of these gene products. These observations are consistent with a necessity for an ongoing need for the gene products in human learning and memory. In addition, in the case of both the ERK/CREB/CBP system and the CaMKII system, there is direct evidence from animal studies that acute inhibition of these systems in adults is sufficient to cause learning deficiencies. These types of considerations suggest a rethinking of our outlook on human learning disorders, changing from the traditional view of them as purely developmental problems to a new view of them as cognitive deficiencies. This sea-change in outlook may be one of the most important outcomes of new and ongoing discoveries concerning the basic signal transduction processes subserving learning and memory.


1. Weeber, E. J., and Sweatt, J. D. (2002). "Molecular neurobiology of human cognition." Neuron 33:845-848.

2. Ozonoff, S. (1999). "Cognitive impairment in neurofibromatosis type 1." Am. J. Med. Genet. 89:45-52.

3. Silva, A. J., Frankland, P. W., Marowitz, Z., Friedman, E., Lazlo, G., Cioffi, D., Jacks, T., and Bourtchuladze, R. (1997). "A mouse model for the learning and memory deficits associated with neurofibromatosis type I." Nat. Genet. 15:281-284.

4. Costa, R. M., Yang, T., Huynh, D. P., Pulst, S. M., Viskochil, D. H., Silva, A. J., and Brannan, C. I. (2001). "Learning deficits, but normal development and tumor predisposition, in mice lacking exon 23a of Nf1." Nat. Genet. 27:399-405.

5. Andersen, L. B., Ballester, R., Marchuk, D. A., Chang, E., Gutmann, D. H., Saulino, A. M., Camonis, J., Wigler, M., and Collins, F. S. (1993). "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. 13:487-495.

6. Zhu, Y., and Parada, L. F. (2001). "A particular GAP in mind." Nat. Genet. 27:354-355.

7. Ohno, M., Frankland, P. W., Chen, A. P., Costa, R. M., and Silva, A. J. (2001). "Inducible, pharmacoge-netic approaches to the study of learning and memory." Nat. Neurosci. 4:1238-1243.

8. Ingram, D. A., Hiatt, K., King, A. J., Fisher, L., Shivakumar, R., Derstine, C., Wenning, M. J., Diaz, B., Travers, J. B., Hood, A., Marshall, M., Williams, D. A., and Clapp, D. W. (2001). "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. 194:57-69.

9. Tong, J., Hannan, F., Zhu, Y., Bernards, A., and Zhong, Y. (2002). "Neurofibromin regulates G protein-stimulated adenylyl cyclase activity." Nat. Neurosci. 5:95-96.

10. Impey, S., Obrietan, K., Wong, S. T., Poser, S., Yano, S., Wayman, G., Deloulme, J. C., Chan, G., and Storm, D. R. (1998). "Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation." Neuron 21:869-883.

11. Roberson, E. D., English, J. D., Adams, J. P., Selcher, J. C., Kondratick, C., and Sweatt, J. D. (1999). "The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus." J. Neurosci. 19:4337-4348.

12. Dufresne, S. D., Bjorbaek, C., El-Haschimi, K., Zhao, Y., Aschenbach, W. G., Moller, D. E., and Goodyear, L. J. (2001). "Altered extracellular signal-regulated kinase signaling and glycogen metabolism in skeletal muscle from p90 ribosomal S6 kinase 2 knockout mice." Mol. Cell. Biol. 21:81-87.

13. Harum, K. H., Alemi, L., and Johnston, M. V. (2001). "Cognitive impairment in Coffin-Lowry syndrome correlates with reduced RSK2 activation." Neurology 56:207-214.

14. Greenough, W. T., Klintsova, A. Y., Irwin, S. A., Galvez, R., Bates, K. E., and Weiler, I. J. (2001).

"Synaptic regulation of protein synthesis and the fragile X protein." Proc. Natl. Acad. Sci. USA 98:7101-7106.

15. Jiang, Y. H., Armstrong, D., Albrecht, U., Atkins, C. M., Noebels, J. L., Eichele, G., Sweatt, J. D., and Beaudet, A. L. (1998). "Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation." Neuron 21:799-811.

16. Hagerman, R. J., and Hagerman, P. J. (2001). "Fragile X syndrome: a model of gene-brain-behavior relationships." Mol. Genet. Metab. 74:89-97.

17. Bardoni, B., Schenck, A., and Mandel, J. L. (2001). "The Fragile X mental retardation protein." Brain Res. Bull. 56:375-382.

18. Zhang, Y. Q., Bailey, A. M., Matthies, H. J., Renden, R. B., Smith, M. A., Speese, S. D., Rubin, G. M., and Broadie, K. (2001). "Drosophila fragile X-related gene regulates the MAP1B homolog Futsch to control synaptic structure and function." Cell 107:591-603.

19. Gu, Y., McIlwain, K., Weeber, E. J., Yamagata, T., Xu, B., Antalffy, B., Reye, C., Yuva-Paylor, L., Armstrong, D., Zoghbi, H., Sweatt, J. D., Paylor, R., and Nelson, D. (2002). "Impaired conditioned fear and enhanced long-term potentiation in Fmr2 knockout mice." J. Neurosci. 22(7):1753-1763.

20. Oike, Y., Hata, A., Mamiya, T., Kaname, T., Noda, Y., Suzuki, M., Yasue, H., Nabeshima, T., Araki, K., and Yamamura, K. (1999). "Truncated CBP protein leads to classical Rubinstein-Taybi syndrome phenotypes in mice: implications for a dominant-negative mechanism." Hum. Mol. Genet. 8:387-396.

21. Hegde, A. N., Inokuchi, K., Pei, W., Casadio, A., Ghirardi, M., Chain, D. G., Martin, K. C., Kandel, E. R., and Schwartz, J. H. (1997). "Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia." Cell 89:115-126.

22. Chain, D. G., Hegde, A. N., Yamamoto, N., Liu-Marsh, B., and Schwartz, J. H. (1995). "Persistent activation of cAMP-dependent protein kinase by regulated proteolysis suggests a neuron-specific function of the ubiquitin system in Aplysia." J. Neurosci. 15:7592-7603.

23. Shahbazian, M. D., Antalffy, B., Armstrong, D. L., and Zoghbi, H. Y. (2002). "Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation." Hum. Mol. Genet. 11:115-124.

24. Bellugi, U., Adolphs, R., Cassady, C., and Chiles, M. (1999). "Towards the neural basis for hypersociability in a genetic syndrome." Neuroreport 10:1653-1657.

25. Donnai, D., and Karmiloff-Smith, A. (2000). "Williams syndrome: from genotype through to the cognitive phenotype." Am. J. Med. Genet. 97:164-171.

26. Korenberg, J. R., Chen, X. N., Hirota, H., Lai, Z., Bellugi, U., Burian, D., Roe, B., and Matsuoka, R. (2000). "VI. Genome structure and cognitive map of Williams syndrome." J. Cogn. Neurosci. 12 Suppl 1:89-107.

27. Meng, Y., Zhang, Y., Tregoubov, V., Janus, C., Cruz, L., Jackson, M., Lu, W. Y., MacDonald, J. F., Wang, J. Y., Falls, D. L., and Jia, Z. (2002). "Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice." Neuron 35:121-133.

28. Bienvenu, T., des Portes, V., McDonell, N., Carrie, A., Zemni, R., Couvert, P., Ropers, H. H., Moraine, C., van Bokhoven, H., Fryns, J. P., Allen, K., Walsh, C. A., Boue, J., Kahn, A., Chelly, J., and Beldjord, C. (2000). "Missense mutation in PAK3, R67C, causes X-linked nonspecific mental retardation." Am. J. Med. Genet. 93:294-298.

29. Schmid, R. S., Pruitt, W. M., and Maness, P. F. (2000). "A MAP kinase-signaling pathway mediates neurite outgrowth on L1 and requires Src-dependent endocytosis." J. Neurosci. 20:4177-4188.

30. Kutsche, K., Yntema, H., Brandt, A., Jantke, I., Nothwang, H. G., Orth, U., Boavida, M. G., David, D., Chelly, J., Fryns, J. P., Moraine, C., Ropers, H. H., Hamel, B. C., van Bokhoven, H., and Gal, A. (2000). "Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation." Nat. Genet. 26:247-250.

31. Allen, K. M., Gleeson, J. G., Bagrodia, S., Partington, M. W., MacMillan, J. C., Cerione, R. A., Mulley, J. C., and Walsh, C. A. (1998). "PAK3 mutation in nonsyndromic X-linked mental retardation." Nat. Genet. 20:25-30.

32. Ridley, A. J. (2001). "Rho family proteins: coordinating cell responses." Trends Cell. Biol. 11:471-477.

33. King, A. J., Sun, H., Diaz, B., Barnard, D., Miao, W., Bagrodia, S., and Marshall, M. S. (1998). "The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338." Nature 396:180-183.

34. Billuart, P., Bienvenu, T., Ronce, N., des Portes, V., Vinet, M. C., Zemni, R., Roest Crollius, H., Carrie, A., Fauchereau, F., Cherry, M., Briault, S., Hamel, B., Fryns, J. P., Beldjord, C., Kahn, A., Moraine, C., and Chelly, J. (1998). "Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation." Nature 392:923-926.

35. Altafaj, X., Dierssen, M., Baamonde, C., Marti, E., Visa, J., Guimera, J., Oset, M., Gonzalez, J. R., Florez, J., Fillat, C., and Estivill, X. (2001). "Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome." Hum. Mol. Genet. 10:1915-1923.

36. Siarey, R. J., Carlson, E. J., Epstein, C. J., Balbo, A., Rapoport, S. I., and Galdzicki, Z. (1999). "Increased synaptic depression in the Ts65Dn mouse, a model for mental retardation in Down syndrome." Neuropharmacology 38:1917-1920.

37. Thiels, E., Urban, N. N., Gonzalez-Burgos, G. R., Kanterewicz, B. I., Barrionuevo, G., Chu, C. T., Oury, T. D., and Klann, E. (2000). "Impairment of long-term potentiation and associative memory in mice that overexpress extracellular superoxide dismutase." J. Neurosci. 20:7631-7639.

38. Rampon, C., Tang, Y. P., Goodhouse, J., Shimizu, E., Kyin, M., and Tsien, J. Z. (2000). "Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMD AR1-knockout mice." Nat. Neurosci. 3:238-244.

39. Costa, R. M., Federov, N. B., Kogan, J. H., Murphy, G. G., Stern, J., Ohno, M., Kucherlapati, R., Jacks, T., and Silva, A. J. (2002). "Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1." Nature 415:526-530.

40. Jiang, Y. H., Armstrong, D., Albrecht, U., Atkins, C. M., Noebels, J. L., Eichele, G., Sweatt, J. D., and Beaudet, A. L. (1998). "Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation." Neuron 21:799-811.

41. Gu, Y., McIlwain, K. L., Weeber, E. J., Yamagata, T., Xu, B., Antalffy, B. A., Reyes, C., Yuva-Paylor, L., Armstrong, D., Zoghbi, H., Sweatt, J. D., Paylor, R., and Nelson, D. L. (2002). "Impaired conditioned fear and enhanced long-term potentiation in Fmr2 knock-out mice." J. Neurosci. 22:2753-2763.

42. Mistry, D. J., Moorman, J. R., Reddy, S., and Mounsey, J. P. (2001). "Skeletal muscle Na currents in mice heterozygous for Six5 deficiency." Physiol. Genomics 6:153-158.

43. Gahtan, E., Auerbach, J. M., Groner, Y., and Segal, M. (1998). "Reversible impairment of long-term potentiation in transgenic Cu/Zn-SOD mice." Eur. J. Neurosci. 10:538-544.

44. Morris, C. A., and Mervis, C. B. (2000). "Williams syndrome and related disorders." Annu. Rev. Genomics Hum. Genet. 1:461-484.

45. Sweatt, J. D. (2001). "Protooncogenes subserve memory formation in the adult CNS." Neuron 31:671-674.

46. Weeber, E. J., and Sweatt, J. D. (2000). "Disruptions of signal transduction pathways in mental retardation: Angelman and Coffin-Lowry syndrome."

Recent Res. Devel. Neurochem. 3:289-299.

Alzheimer's Disease J. David Sweatt, Acrylic on canvas, 2002

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