Consequences of NMDA receptor deficiency can be rescued in the adult brain
Mol Psychiatry. 2020-08-17; :
DOI: 10.1038/s41380-020-00859-4
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Consequences of NMDA receptor deficiency can be rescued in the adult brain.
Mielnik CA(1), Binko MA(2)(3), Chen Y(1)(4), Funk AJ(5), Johansson EM(6), Intson K(1), Sivananthan N(1), Islam R(2), Milenkovic M(1), Horsfall W(1), Ross RA(1), Groc L(6), Salahpour A(1), McCullumsmith RE(5), Tripathy S(4), Lambe EK(2)(7)(8), Ramsey AJ(9)(10).
Author information:
(1)Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
(2)Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
(3)University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
(4)Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health,
Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1L8, Canada.
(5)Department of Neurosciences, University of Toledo, Toledo, OH, 43614, USA.
(6)Interdisciplinary Institute for NeuroScience (IINS) CNRS, Université Bordeaux Segalen, 33000, Bordeaux, France.
(7)Department of OBGYN, University of Toronto, Toronto, ON, M5G 1E2, Canada.
(8)Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1L8, Canada.
(9)Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada. .
(10)Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada. .
N-methyl-D-aspartate receptors (NMDARs) are required to shape activity-dependent connections in the developing and adult brain. Impaired NMDAR signalling through genetic or environmental insults causes a constellation of neurodevelopmental disorders that manifest as intellectual disability, epilepsy, autism, or schizophrenia. It is not clear whether the developmental impacts of NMDAR dysfunction can be overcome by interventions in adulthood. This question is paramount for neurodevelopmental disorders arising from mutations that occur in
the GRIN genes, which encode NMDAR subunits, and the broader set of mutations that disrupt NMDAR function. We developed a mouse model where a congenital loss-of-function allele of Grin1 can be restored to wild type by gene editing with Cre recombinase. Rescue of NMDARs in adult mice yields surprisingly robust improvements in cognitive functions, including those that are refractory to treatment with current medications. These results suggest that neurodevelopmental disorders arising from NMDAR deficiency can be effectively treated in adults.