Consequences Of NMDA Receptor Deficiency Can Be Rescued In The Adult Brain

Abstract

NMDA receptors (NMDAR) are important in the formation of activity-dependent connections in the brain. In sensory pathways, NMDAR disruption during discrete developmental periods has enduring effects on wiring and function. Yet, it is not clear whether NMDAR-limited critical periods exist for higher-order circuits governing mood and cognition. This question is urgent for neurodevelopmental disorders, like schizophrenia, that have NMDAR hypofunction and treatment-resistant cognitive symptoms. As proof of concept, we developed a novel mouse model where developmental NMDAR deficits can be ameliorated by inducible Cre recombinase. Rescue of NMDARs in either adolescence or adulthood yields surprisingly strong improvements in higher-order behavior. Similar levels of behavioral plasticity are observed regardless of intervention age, with degree of plasticity dependent on the specific behavioral circuit. These results reveal higher-order brain function as amenable to treatment in adulthood and identify NMDAR as a key target for cognitive dysfunction.