SU10. Behavioral Characteristics of a DISC1 Knockout Rat Model

Abstract

Background: The population carrying Disrupted In Schizophrenia 1 (DISC1) mutant gene(s) have a higher risk to develop schizophrenia and other mental disorders, eg, bipolar disorder, major depression, and autism. One hypothesis is that the different outcome is a result of the pleiotropic effect of DISC1 allelic variation; depending on the location and type of sequence change, there exists selective effects on specifc protein interactions, and consequentially impact on the DISC1 pathway-mediated brain development, function, and behaviors. Methods: Here, we report how a deletion on the DISC1 exon2 in rat affects its behaviors and psychological functions. We tracked the behavioral and psychologically functional development through the birth to early adulthood. Multiple functional domains, including social function, basic cognition, affective state, and drug sensitivity, were assessed. Results: Starting on PND12 and 13, we compared the mutant rats (n = 12 per sex, 24 in total) with the wild-type (WT) control (n = 6 per sex, 12 in total) for pup ultrasonic vocalization (USV) and its maternal potentiation. Results showed that mutant rats emitted fewer long and fewer frequency-modifed USVs after a brief separation from mothers. However, no difference on maternal potentiation between the 2 groups was found. On PND 42, we tested the rats on an elevated plus maze task to assess their anxiety levels. There was a trend that the mutant rats spent less time on open arms indicating they were more anxious. On PND 47, we tested rats in a social/object/location preference task; a task that was modifed from traditional preference tasks. The mutant rats were not showing defcits in relevant social and memory functions, as they spent an equivalent amount of time on exploring new object/location/social partners compared to the WT controls. The rats were also tested for prepulse inhibition (an index of pre-attentive function), fear-potentiated startle (acute threat/fear), and latent inhibition on PND 49-54, no major defcits were noted, although more data are needed to draw a conclusion. On PND 61-65, the rats were tested for locomotion and amphetamine-induced hyperlocomotion with challenging dosage on 0.5 and 1.0 mg/kg. Results revealed that mutant female rats generated more locomotion compared to the female WT rats in the 1 hour after administering amphetamine under both dose regimens. In addition, mutant female rats seemed to have innate hyperlocomotion compared to their male counterparts. Conclusion: Overall, this research provides some insights about how a mutation on DISC1 exon2 affects multiple behaviors in rats. Pup USV in the early life and drug sensitivity in early adulthood seem to be mostly affected. More studies are needed to provide a comprehensive understanding of the impacts of DISC1 knockout on psychological functions.