Abstract
Highlights GluN1 inducible rescue mice allow recovery of functional NMDA receptors in a neurodevelopmental model of schizophrenia.
Rescue in adolescent or adult mice achieves a similar level of functional recovery.
Cortically-mediated behaviors show complete or near complete rescue, but subcortically-mediated behaviors show limited rescue.
Higher-order brain function appears amenable to treatment in adulthood and surprisingly unencumbered by critical period.
SUMMARY 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.
Footnotes
Amy Ramsey, 1 King’s College Circle, Room 4302 Medical Sciences Building, Toronto, ON M5S 1A8 Canada, (416) 978-2509 a.ramsey{at}utoronto.ca