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Consequences of NMDA Receptor Deficiency Can Be Rescued in the Adult Brain

75 Pages Posted: 5 Apr 2018 Sneak Peek Status: Review Complete

See all articles by Catharine A. Mielnik

Catharine A. Mielnik

University of Toronto - Department of Pharmacology and Toxicology

Yuxiao Chen

University of Toronto - Department of Pharmacology and Toxicology

Mary A. Binko

University of Toronto, Faculty of Medicine, Department of Physiology

Rehnuma Islam

University of Toronto, Faculty of Medicine, Department of Physiology

Marija Milenkovic

University of Toronto - Department of Pharmacology and Toxicology

Wendy Horsfall

University of Toronto - Department of Pharmacology and Toxicology

Ali Salahpour

University of Toronto - Department of Pharmacology and Toxicology

Evelyn K. Lambe

University of Toronto, Faculty of Medicine, Department of Physiology

Amy J. Ramsey

University of Toronto - Department of Pharmacology and Toxicology

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Abstract

NMDA receptors (NMDAR) are important in the formation of activitydependent 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.

Suggested Citation

Mielnik, Catharine A. and Chen, Yuxiao and Binko, Mary A. and Islam, Rehnuma and Milenkovic, Marija and Horsfall, Wendy and Salahpour, Ali and Lambe, Evelyn K. and Ramsey, Amy J., Consequences of NMDA Receptor Deficiency Can Be Rescued in the Adult Brain (2018). Available at SSRN: https://ssrn.com/abstract=3155924 or http://dx.doi.org/10.2139/ssrn.3155924
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Catharine A. Mielnik (Contact Author)

University of Toronto - Department of Pharmacology and Toxicology

1 King's College Circle
Medical Sciences Building, Room 4207
Toronto, Ontario M5S 1A8
Canada

Yuxiao Chen

University of Toronto - Department of Pharmacology and Toxicology

1 King's College Circle
Medical Sciences Building, Room 4207
Toronto, Ontario M5S 1A8
Canada

Mary A. Binko

University of Toronto, Faculty of Medicine, Department of Physiology

Medical Sciences Building, 3rd Floor
1 King's College Circle
Toronto
Canada

Rehnuma Islam

University of Toronto, Faculty of Medicine, Department of Physiology

Medical Sciences Building, 3rd Floor
1 King's College Circle
Toronto
Canada

Marija Milenkovic

University of Toronto - Department of Pharmacology and Toxicology

1 King's College Circle
Medical Sciences Building, Room 4207
Toronto, Ontario M5S 1A8
Canada

Wendy Horsfall

University of Toronto - Department of Pharmacology and Toxicology

1 King's College Circle
Medical Sciences Building, Room 4207
Toronto, Ontario M5S 1A8
Canada

Ali Salahpour

University of Toronto - Department of Pharmacology and Toxicology

1 King's College Circle
Medical Sciences Building, Room 4207
Toronto, Ontario M5S 1A8
Canada

Evelyn K. Lambe

University of Toronto, Faculty of Medicine, Department of Physiology

Medical Sciences Building, 3rd Floor
1 King's College Circle
Toronto
Canada

Amy J. Ramsey

University of Toronto - Department of Pharmacology and Toxicology ( email )

1 King's College Circle
Medical Sciences Building, Room 4207
Toronto, Ontario M5S 1A8
Canada

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