Transgenic animal technology (knockdown and out), from DNA microinjection to gene targeting and cloning, resulting in 'loss-of-function' mutants can be used to clarify the role of molecules thought to be involved in development and structural maintenance of the nervous system. Transgenic models of human disease are used extensively to assess the validity of therapeutic applications before clinical trials although there is an active debate as to the utility of transgenics in drug discovery.25
The most compelling evidence of a link between genetic variation and the role of the SERT in depression and anxiety led to SERT knockout mice that show increased anxiety-like behaviors, reduced aggression, and exaggerated stress responses. Appropriate functioning of SERT and monoamine oxidase A (MAO-A) during early life appear critical to the normal development of these systems. MAO-A and SERT knockout mice mimic in some respects the consequences of reduced genetic expression in humans. MAO-A knockout mice exhibit high levels of aggression, similar to the elevated impulsive aggression seen in humans lacking this gene. SERT knockout mice may thus represent a more exaggerated version of the reduced SERT expression found in certain subjects, and a partial model of the increased vulnerability to anxiety and affective disorders seen in human subjects with the low expressing allele. Table 5 lists some of the genetically modified mice that have been reported to show depressive or antidepressant-like behavior in simple behavioral tests, e.g., Porsolt FST.
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