Inherited Disorders of Human Memory

Mental Retardation Syndromes

I. Neurofibromatosis, Coffin-Lowry Syndrome, and the ras/ERK Cascade II. Angelman Syndrome

III. Fragile X Syndromes

A. Fragile X Mental Retardation Syndrome Type 1

B. Fragile X Mental Retardation Type 2

IV. Summary

As we discussed in the first chapter, our great capacity for learning and remembering plays an enormous role in forming our human potential. Moreover, our personal experiences, where we have learned and remembered specific items and events, define us as individuals. These truths are nowhere more evident than when we consider individuals with pronounced learning and memory deficits, present from birth. In this chapter, we consider human mental retardation syndromes and their underlying molecular basis. In some intellectually satisfying instances, we will actually be able to tie mechanisms for these disorders back into fundamental mechanisms for synaptic plasticity and learning that we have already discussed.1

1Parts of this chapter are adapted from Weeber and Sweatt (1).

There is another point that is important to make in the context of this chapter. Of all the various areas of cognitive neurobiology, the field of learning and memory has advanced the farthest into studies at the molecular level, based on a reductionist approach of using model systems simpler than the human. But how can one bridge the enormous distance from specific molecules to human cognition? Over the past few years, a number of groups, including research teams at Baylor College of Medicine, UCLA, Johns Hopkins University, and the University of Illinois to name a few specific examples, have undertaken to bridge this gap by studying naturally occurring human mental retardation syndromes. The philosophy of the approach is to use identified human genetic mutations that result in mental retardation and learning disorders as an entrée to beginning to understand the molecular basis of human cognition. As a practical matter, this translates into taking an identified human gene linked to a mental retardation syndrome and making knockout and transgenic mouse models. These models are then used to generate insights into the underlying molecular and cellular basis for the defect. The rationale is that this gives one insights into the analogous "knockout humans" and hence gives insights into the molecular neurobiology of human cognitive processing. Some specific examples of mental retardation syndromes where this approach has been applied are given in Table 1.

Even though this approach is at a very early stage, it is interesting that different studies of this sort have already begun to converge on two common signal transduc-tion cascades as being involved in human learning and memory: the ras/ERK cascade and its associated upstream regulators and downstream targets (see Figure 1) and the CaMKII system. In the first section of this chapter, I will describe exciting recent findings implicating dysfunction of the ras/ERK cascade in human mental retardation syndromes. I should emphasize that several of the ideas I will present in this section, where I present potential mechanistic links between various different human mental retardation syndromes, are at best educated guesses. However, I simply cannot resist beginning to synthesize a unified picture of critical molecular events in human learning. This extends perfectly the sorts of studies we have been discussing where learning was studied in rodent models.

In the second section of this chapter, I will discuss recent findings from my lab and Alcino Silva's lab implicating CaMKII in a form of human mental retardation. In the final section, I will discuss fragile X retardation syndromes, and we will see yet another instance of the basic studies of synaptic plasticity running head-on into studies of a human learning disorder. In this last section I will highlight work from Bill Greenough's lab, among others' that has begun to tie mechanisms of local dendritic protein synthesis in with molecular mechanisms of fragile X mental retardation type 1.

Before getting down to the serious business of this chapter, I want to relate a personal anecdote that illustrates the funny way that things sometime evolve in science. Alcino Silva and I are of the same scientific generation and, as such, have been competitors in a certain sense—we both set out as naive, optimistic young scientists to "solve memory," of course ideally before anyone else did. While I'm oversimplifying, Alcino basically staked his claim with CaMKII and I grabbed MAP kinases, each of us working on basic mechanisms of synaptic plasticity and memory that were described earlier in this book. Essentially as side projects, Alcino started working on neurofibromatosis mental retardation and my lab started working on Angelman Mental Retardation Syndrome (AS). In the first section of this chapter, I will describe work from Alcino's lab, highlighting the likely importance of MAP kinase in human memory, based on his studies of Neurofibromatosis. In the second section I am going to describe studies from my lab suggesting the importance of CaMKII in human memory, based on our studies of the Angelman Syndrome. In my mind, these are very satisfying examples of how following the clues that Nature gives us will always lead us to common ground.

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