Box 1

MOUSE TRAPS—CAVEATS TO THE USE OF KNOCKOUT ANIMALS

Sometime in 1995, Joey English discovered that ERK MAP kinases are activated with LTP-inducing stimulation. Because no inhibitor of ERK activation that would allow testing the necessity of the phenomenon for LTP induction was available at that time, I broached the issue with Joey of generating ERK knockout mice. I'll never forget Joey's response: "Those animals will never make it past the eight-cell stage." Here it is eight years later, and still no ERK2 knockout animal is available, so Joey may well have been correct. His point was that some signal transduction processes are so fundamentally important for general cellular regulation that you will never be able to obtain a knockout mouse missing those components.

This is just one example of a number of caveats to using the knockout/transgenic mouse approaches in neurobiology. In fact, the overall complexity of the CNS and the functions it serves make this the worst-case scenario for the application of genetic engineering technology. Of course, it's also the most interesting, important, and powerful application of the technology! Given this Catch-22, it is widely recognized these days that in most cases we must simply bite the bullet and go ahead and use genetically modified animals wherever possible, keeping in mind the important caveats that go along with the approach. In the table I've listed some of the documented pitfalls to the approach. Please note that the table is not comprehensive, simply illustrative.

I've also added a brief section on some established ways around known traps. These include some of the emerging technologies that allow inducible genetic deletions and/or brain-subregion specific manipulations, in order to get around some of the problems listed in the first part of the table.

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