Research paper on Developmentally Determined Expression of GluN2B and GluN2A-Containing Receptors and Balanced Allosteric Modulatory Approaches: Targeted NMDA Receptor Interventions for Autism

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Title: Developmentally Determined Expression of GluN2B and GluN2A-Containing Receptors and Balanced Allosteric Modulatory Approaches: Targeted NMDA Receptor Interventions for Autism

Abstract: NMDA receptor hypofunction, also known as NMDA receptor dysfunction, and/or disruption of the delicate balance between activation mediated by GluN2B-subtype and GluN2A-subtype-containing NMDA receptors have been linked to a number of ASD risk alleles. Importantly, despite the fact that each of these risk alleles affects NMDA receptor activation in a different way, they all have the same pathogenic effects on the highly regulated NMDA receptor activation. Sequence variations, protein termination variations, and copy number variations frequently cause NMDA receptor activation disturbances that are cell- and region-specific. Translational therapeutic NMDA receptor agonist interventions must be specific, selective, and facilitate NMDA receptor activation in a physiological manner (i.e., mimic endogenous glutamate and glycine/D-serine released in response to salient and relevant socio-cognitive provocations within discrete neural circuits). These interventions may require chronic administration. Importantly, knockout mice with no expression of the harmful genes and mice with haploinsufficient expression of the genes are frequently useful models to test the potential effectiveness of promising pharmacotherapeutic approaches. The Review takes into account various examples of “illness” genes, their pathogenic effects on NMDA receptor activation, and, when available, the outcomes of studies of impaired sociability in mouse models. These studies include “proof of principle/proof of concept” experiments examining NMDA receptor agonist interventions and the development of promising positive allosteric modulators (PAMs), which serve as support and models for creating an inventory of PAMs and negative allosteric modulators. It is possible that patients will be given selective PAMs and NAMs individually or in combination based on their genotype in an effort to potentiate and/or restore the balance between activation mediated by GluN2B-subtype and GluN2A-subtype containing NMDA receptors that has been upset.

Keywords: NMDA receptor; autism spectrum disorder; positive allosteric modulators; negative allosteric modulators

Paper Quality: SCOPUS / Web of Science Level Research Paper

Subject: Biomolecules

Writer Experience: 20+ Years

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