CLINICALLY PREDICTIVE MODULATION OF COGNITIVE IMPAIRMENTS IN MOUSE TOUCHSCREEN TASKS

Abstract Background Cognitive deficits in individuals with schizophrenia present a significant barrier to maintaining interpersonal relationships, employment, and independent living. Moderate to severe impairments have been found in cognitive domains including working memory, attention, learning and executive function. Despite the clear impact on functional outcomes, there are currently no approved treatments for cognitive impairments associated with schizophrenia (CIAS). Extensive efforts to develop pro-cognitive medicines, both for CIAS and other neuropsychiatric disorders, have repeatedly led to clinical trials that do not reflect the efficacy predicted in preclinical models. Aims & Objectives The rodent touchscreen platform has begun to bridge the translational gap between preclinical and clinical assessments of cognitive function. However, to date there has been no pharmacological validation of whether these tests are stringent enough to be clinically predictive and can therefore improve translation of CIAS treatments. Method Here, we use an NMDA receptor antagonist mouse model (acute low-dose administration) that we have validated for cognitive deficits in working memory performance on the rodent trial-unique delayed nonmatch-to-location touchscreen task. We then measured the effect of 1) current standard of care (aripiprazole and olanzapine), 2) failed investigational new drugs (IND) for CIAS (atomoxetine and encenicline), and 3) a current IND for schizophrenia (xanomeline) on working memory and attentional impairments. Results For the first time, we demonstrate a translational method for cognitive assessment in mice that can distinguish drugs with clinical efficacy from those without. Discussion & Conclusion These results provide critical insight into the predictive validity of our preclinical assay and cognitive deficit model, and have significant implications for the development and translation of novel pro-cognitive medicines.