Consequences of NMDA receptor deficiency can be rescued in the adult brain

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.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/140343 doi: bioRxiv preprint first posted online May. 20, 2017; 2 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.

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…These studies suggest that the phenotype determined in heterologous systems is predictive of that observed in neurons. Similarly, mice expressing reduced levels of GRIN1 show deficits similar to some patients (Intson et al, 2019;Mielnik et al, 2020), and mice lacking GRIN2A show hyperexcitability (Salmi et al, 2018(Salmi et al, , 2019, consistent with patients showing seizures with GRIN2A truncations (Lemke et al, 2013).…”

“…Chronic treatment with either dextromethorphan, radiprodil (GluN2B-selective NAM), or Nuedexta (dextromethorphan 1 quinidine) of homozygous mice hosting a GRIN2A variant encoding S644G significantly delayed the onset of lethal seizures (Amador et al, 2020). Treatment of a loss-of-function Grin1 mouse with expression of wild-type gene improved cognitive function, suggesting it may be possible to mitigate some aspects of neurodevelopmental disorders arising from variants that reduce receptor expression (Mielnik et al, 2020). These preclinical studies provide evidence that treatment may be possible using clinically useful pharmacological and genetic approaches.…”

NMDAR Hypofunction Animal Models of Schizophrenia

“…In the NR1-KD mice, the hypomorphic insertion mutation could be excised in the Cre recombinase-dependent manner to restore NR1 in a temporal-regulated fashion. This allowed to investigate behavioral phenotypic rescue at different stages of development upon global restoration of NMDARs (Mohn et al, 1999; Mielnik et al, 2017). The mice with inducible NR1 rescue during adolescence or in adulthood achieved similar levels of functional recovery in some of cognitive deficits and negative symptoms-related behavioral changes, with cortically-mediated behaviors completely or nearly rescued.…”

“…However, subcortically-mediated behaviors, such as hyperlocomotor activity and anxiety-related behaviors were only partially rescued. This suggested that higher-order brain functions are potentially more amenable to treatment in adulthood and unencumbered by critical period (Mielnik et al, 2017). Overexpressing NR2B in aged wild type mice was able to rescue age-associated impairments in hippocampal-dependent spatial memory.…”

Suppressed prefrontal neuronal firing variability and impaired social representation in IRSp53-mutant mice

“…Dysfunctions of NMDA receptors have been associated with social deficits in mouse models of psychiatric disorders (Chung et al, 2019;Lee et al, 2021b;Mielnik et al, 2021;Shin et al, 2020;Won et al, 2012;XiangWei et al, 2018). In addition, IRSp53-KO mice show NMDAR hyperfunction and memantine treatment-dependent rescue of social deficits (Bobsin and Kreienkamp, 2015;Chung et al, 2015;Kim et al, 2009).…”