The GluN2C/D-specific positive allosteric modulator CIQ rescues delay-induced working memory deficits in mice

Working memory is of short duration and is, therefore, particularly sensitive to time delays. Moreover, NMDA receptors are significantly involved in working memory. In the present study, we tested whether a commonly used measure of working memory, spontaneous alternation in the Y-maze, is sensitive to time delays and, if so, whether impairments due to time-delay can be rescued by treatment with CIQ, a positive allosteric modulator of the GluN2C/D subunits of NMDA receptor. Our results indicate that the effects of time delay do depend on the performance of the individual mice under basal condition. Those mice that performed well under basal conditions showed impaired spontaneous alternations when tested with a 45-s delay. Treatment with CIQ resulted in an improvement of spontaneous alternations, regardless of delay, sex, or basal performance. On the one hand, our study shows that repeated measures of individual behavior can better control the effects of confounding factors such as time delays. On the other hand, our study also highlights the potential of GluN2C/D-specific positive allosteric modulators in the treatment of human disorders associated with working memory deficits, such as schizophrenia.