Genetic Models

Attempts have been made to produce transgenic mouse models with a reasonable degree of construct validity. For example, neurotransmitter receptors believed to be relevant to schizophrenia including D1-D5 DA and NMDA receptors have been selectively knocked out or knocked down. One interesting example of this approach is the near complete knockdown of the obligatory NR1 subunit of the NMDA receptor to approximately 5% of normal expression levels.37 This decrease in functional NMDA receptor expression produces increased spontaneous hyperlocomotion and social deficits that respond to antipsychotics. While this model appears to hold face validity, there is actually little evidence for decreased NMDA receptors in schizophrenia. Therefore, the overall validity of this model is still questionable. As discussed above, the current state of the human genetics of schizophrenia indicates that this is a nonhomogeneous multifactorial disorder. Therefore, there is not likely to be a 'schizophrenic mouse' model. While selective alteration of genes implicated in schizophrenia either on the basis of pathophysiology or genetic linkage may provide some insight into disease pathogenesis, this approach will likely result in incomplete models of the disorder. These models must be interpreted with great care as they carry all of the usual caveats of genetic models, including the potential for compensatory developmental changes in noninducible knockouts.

It is important to note that almost all of the currently available models and assays focus on the positive symptoms of schizophrenia. This has been a fruitful path for developing clozapine-like molecules with increase safety margins. However, this approach has led to the generation of therapies that do not alter the debilitating negative or cognitive symptoms of the disease. Currently there are no accepted models of negative or cognitive symptoms; however, as attention focuses on these more refractory symptoms of schizophrenia, it will be crucial to better characterize existing models and begin to develop new models to meet the obvious challenge of generating novel drugs that address these symptoms.

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