Abstract
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.
Highlights
Greater than 1% of children are born with a neurodevelopmental disorder [1], including diagnoses of autism spectrum disorder and pervasive developmental delay [2]
To address whether developmental insults to the N-methyl-D-aspartate-type glutamate receptors (NMDARs) system can be overcome with adult intervention, we developed a mouse model with a congenital global lossof-function allele of Grin1, that could be globally genetically restored, temporally, by gene editing with Cre recombinase
To directly answer whether the developmental consequences of NMDAR deficiency could be rescued in adults, we generated mice with a reversible hypomorphic mutation in Grin1, the essential subunit of all NMDARs
Summary
Greater than 1% of children are born with a neurodevelopmental disorder [1], including diagnoses of autism spectrum disorder and pervasive developmental delay [2]. Whole-exome sequencing has revolutionised diagnostic assessment and has identified hundreds of genes that can cause intellectual disability and developmental delay through transmitted and de novo variants [3]. Through whole-exome sequencing, a new syndrome called GRIN disorder has been identified that is caused by mutations in one of the seven GRIN genes that encode subunits for N-methyl-D-aspartate-type glutamate receptors (NMDARs). Deleterious missense and nonsense variants in GRIN1, GRIN2A-D, and GRIN3A-B cause encephalopathies that are sometimes first diagnosed as intellectual disability, global developmental delay, epilepsy, autism, and/or schizophrenia [4]. Regardless of the nature of the mutation, patients with these deleterious variants have a similar syndrome of intellectual disability, and additional symptoms such as epilepsy, autism, cortical visual impairment, and movement disorders [4]
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