Targeting genes and proteins in the analysis of learning and memory: caveats and future directions.

Gene targeting using homologous recombination in embryonic stem (ES) cells and transgenic approaches in general allow one to precisely manipulate single genes and investigate their in vivo function in the mouse. Geneticists argue that these techniques are superior to pharmacological approaches as they obviate the lack of highly specific pharmacological agents in the study of brain function and behavior. However, by now it has become clear that transgenic approaches also have some limitations. One problem is spatial and temporal specificity of the genetic manipulation. The other is the possibility that the introduced genetic alteration gives rise to complex, secondary phenotypic changes. This may be a disadvantage in the functional analysis of genes associated with learning and memory especially if the gene of interest plays roles in embryonic development of the brain as well as in adult neural function. Examples of such genes include, but are not limited to, those encoding neurotrophins, cell adhesion molecules, and protein kinases. Second generation gene targeting with inducible and cell type restricted knock-out, or transgenic approaches with inducible gene expression systems, will solve some problems. However, at present these strategies also suffer from difficulties inherent to the traditional knock-out. Several strategies alternative to transgenic approaches are also available. Antisense oligonucleotides, antibodies, or pharmacological agents may be used to manipulate molecular events at the transcription, translation, or protein function levels. I review these strategies briefly and suggest yet another approach: protein targeting with the use of recombinant immunoadhesins. I suggest that this latter approach has the specificity of gene targeting but lacks some of its disadvantages.