Knockout and Mutant Rats

Rats have been extensively used to explore the brain mechanisms underlying psychiatric disorders. However, due to a lack of sufficient tools for the generation of knockout or mutant rats, there has been a general lag in the understanding of genetic factors in psychiatric and neurodevelopmental disorders, compared to other popular experimental animal models. Recently, several mutant and knockout rats have been generated using N -ethyl-N -nitrosourea (ENU)-driven target selected mutagenesis. Two of them, the serotonin transporter knockout (SERT^−/− ) rat and the dopamine D1 receptor mutant (DRD1^−/− ) rat, are described in relation to four important (neurodevelopmental) psychiatric disorders: depression, autism, schizophrenia and drug addiction. It has been shown that the SERT^−/− rats display increased stress-sensitivity, reduced social approach, reduced impulsivity, and increased cocaine self-administration, but no change in sensorimotor integration has been found. These characteristics could potentially make the SERT^−/− rat extremely valuable to improv the understanding of mechanisms underlying depression, autism and drug addiction. Furthermore, preliminary data show that the DRD1^−/− rat shows alterations in locomotor activity, is less responsive to psychostimulants, displays deficits in working memory, and may be impaired in sensorimotor integration. These data argue that the DRD1^−/− rat models symptoms of schizophrenia as well as drug addiction. Experiments are underway to identify the underlying neuronal mechanisms. Collectively, these findings illustrate that knockout and mutant rats are very valuable in modeling human psychiatric disorders. Furthermore, exploitation of the rat’s advantages in measuring complex cognitive functions will complement mouse knockout studies. In the future, research using knockout and mutant rats is expected to reveal the novel targets in the treatment of psychiatric disorders, to be very helpful in the development of new therapies and the identification of risk groups based on genetic background.