The Postgenomic Era. Genetic Knockout
Concerted work of brain mediators and modulators forms the foundation for the emotional state and behavior of animals and humans
Concerted work of brain mediators and modulators forms the foundation for the emotional state and behavior of animals and humans. Emotions as well as all the known forms of behavior—aggression, sexual behavior, sleep and wake, alcohol and drug addictions—are realized via certain mediator systems with involvement of various receptor types for these mediators. The unexampled International Human Genome and Mouse Genome Sequencing Consortiums have demonstrated a considerable similarity between these genomes and made the mouse a favorite genetic object. Scientists involved in studying the main behavior regulator, the brain, have found revolutionary opportunities connected with the astounding success in decoding the gene structure and elaborating methods for creating transgenic and knockout mice.
The strategy for genetic knockout provides for obtaining mouse strains with an irreversible damage of a particular gene and, correspondingly, the absence of the specific protein—the receptor for mediator or an enzyme involved in its metabolism—in the animal organism. This methodology has generated an intense interest, and has resulted in over a thousand mouse strains lacking a certain individual gene. The most important advantage of the genetic knockout strategy is that it models certain types of hereditary neuropathologies. In particular, Brunner in the mid-1990s descried a large Dutch family with some men displaying mental deficiency and impulsive aggression. It was found that these men carried a point mutation in the exon 8 of monoamine oxidase A (MAO-A) structural gene, localized to the X chromosome; this protein is among the main enzymes involved in the catabolism of serotonin, dopamine, and norepinephrine. A year later, a French research team from the Curie Institute created a strain of transgenic mice with irreversibly damaged MAO-A gene. It is of fundamental importance that the mice of the strain lacking MAO-A gene displayed the changed levels of serotonin, dopamine, norepinephrine, and their metabolites in the brain as well as high aggressiveness, similar to those described for the point mutation of MAO-A gene in human cases. According to our studies, characteristic of the mice with MAO-A knockout is a decrease in exploratory behavior and increase in various types of aggressive behavior. An important specific feature of the knockout mice is their asociality. The “normal” mice fight intensively only for the first hours after a new group is formed, whereupon a certain hierarchy is established in the community and no more cruel fights happen. With the MAO-A knockouts, the fights continue, killing some of the animals. Another specific feature of the mice lacking MAO-A gene is a decreased response to the main types of acute stress and chronic stress.
The important inference suggested by the already known facts on knockout mice is that the absence of a single receptor or enzyme, important as it is for the functioning of several mediator systems, such as MAO-A, does not disorganize all the functions regulated by these mediators. The strategy of genetic knockout displays a distinct Mendelian pattern: one gene–one protein. Disruption of a gene encoding a certain protein leads to a complete absence of the corresponding protein, an enzyme or a receptor, in the body. However, another axiom—one gene, one disorder (Plomin et al., 1994)—as a rule, does not hold true.
This corresponds to the concept widespread in both genetics and physiology that any complex physiological function or behavior is regulated by a gene ensemble rather than a single gene and, correspondingly, by at least several mediator systems. All this demonstrates that regulation of any adaptively significant type of behavior is intricate and multifactorial and that the organism possesses a great compensatory potential. Thus, the knockout mice are not only a unique model for studying the hereditary mental pathologies, but also a valuable model for detecting the corresponding compensatory mechanism.