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

被引:14
作者
Deutsch, Stephen, I [1 ]
Luyo, Zachary N. M. [2 ]
Burket, Jessica A. [2 ,3 ]
机构
[1] Eastern Virginia Med Sch, Dept Psychiat & Behav Sci, 825 Fairfax Ave,Suite 710, Norfolk, VA 23507 USA
[2] Christopher Newport Univ, Program Neurosci, Newport News, VA 23606 USA
[3] Christopher Newport Univ, Dept Mol Biol & Chem, Newport News, VA 23606 USA
关键词
NMDA receptor; autism spectrum disorder; positive allosteric modulators; negative allosteric modulators; CYCLOSERINE IMPROVES SOCIABILITY; DENDRITIC SPINE DEVELOPMENT; MOUSE MODEL; STEREOTYPIC BEHAVIORS; SPECTRUM DISORDERS; SCHIZOPHRENIA; PATIENT; INTERNEURONS; NEUROBEACHIN; HIPPOCAMPUS;
D O I
10.3390/biom12020181
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Various ASD risk alleles have been associated with impairment of NMDA receptor activation (i.e., NMDA Receptor Hypofunction) and/or disturbance of the careful balance between activation mediated by GluN2B-subtype and GluN2A-subtype-containing NMDA receptors. Importantly, although these various risk alleles affect NMDA receptor activation through different mechanisms, they share the pathogenic consequences of causing disturbance of highly regulated NMDA receptor activation. Disturbances of NMDA receptor activation due to sequence variants, protein termination variants and copy number variants are often cell-specific and regionally selective. Thus, translational therapeutic NMDA receptor agonist interventions, which may require chronic administration, must have specificity, selectivity and facilitate NMDA receptor activation in a manner that is physiologic (i.e., mimicking that of endogenously released glutamate and glycine/D-serine released in response to salient and relevant socio-cognitive provocations within discrete neural circuits). Importantly, knockout mice with absent expression and mice with haploinsufficient expression of the deleterious genes often serve as good models to test the potential efficacy of promising pharmacotherapeutic strategies. The Review considers diverse examples of "illness" genes, their pathogenic effects on NMDA receptor activation and, when available, results of studies of impaired sociability in mouse models, including "proof of principle/proof of concept" experiments exploring NMDA receptor agonist interventions and the development of promising positive allosteric modulators (PAMs), which serve as support and models for developing an inventory of PAMs and negative allosteric modulators (NAMs) for translational therapeutic intervention. Conceivably, selective PAMs and NAMs either alone or in combination will be administered to patients guided by their genotype in order to potentiate and/or restore disrupted balance between activation mediated by GluN2B-subtype and GluN2A-subtype containing NMDA receptors.
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页数:31
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