Sex-Dependent Attentional Impairments in a Subchronic Ketamine Mouse Model for Schizophrenia

Background: The development of more effective treatments for schizophrenia targeting cognitive and negative symptoms has been limited, partly due to a disconnect between rodent models and human illness. Ketamine administration is widely used to model symptoms of schizophrenia in both humans and rodents. In mice, subchronic ketamine treatment reproduces key dopamine and glutamate dysfunction; however, it is unclear how this translates into behavioral changes reflecting positive, negative, and cognitive symptoms. Methods: In male and female mice treated with either subchronic ketamine or saline, we assessed spontaneous and amphetamine-induced locomotor activity to measure behaviors relevant to positive symptoms, and used a touchscreen-based progressive ratio task of motivation and the rodent continuous performance test of attention to capture specific negative and cognitive symptoms, respectively. To explore neuronal changes underlying the behavioral effects of subchronic ketamine treatment, we quantified expression of the immediate early gene product, c-Fos, in key corticostriatal regions using immunofluorescence. Results: We showed that spontaneous locomotor activity was unchanged in male and female subchronic ketamine–treated animals, and amphetamine-induced locomotor response was reduced. Subchronic ketamine treatment did not alter motivation in either male or female mice. In contrast, we identified a sex-specific effect of subchronic ketamine on attentional processing wherein female mice performed worse than control mice due to increased nonselective responding. Finally, we showed that subchronic ketamine treatment increased c-Fos expression in prefrontal cortical and striatal regions, consistent with a mechanism of widespread disinhibition of neuronal activity. Conclusions: Our results highlight that the subchronic ketamine mouse model reproduces a subset of behavioral symptoms that are relevant for schizophrenia.