Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, 825 Fairfax Avenue, Suite 710, Norfolk, VA 23507, USA.
Program in Neuroscience, Christopher Newport University, Newport News, VA 23606, USA.
Biomolecules. 2022 Jan 22;12(2):181. doi: 10.3390/biom12020181.
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.
各种 ASD 风险等位基因与 NMDA 受体激活的损害（即 NMDA 受体功能低下）和/或 GluN2B 亚基和 GluN2A 亚基包含的 NMDA 受体激活介导的平衡紊乱有关。重要的是，尽管这些不同的风险等位基因通过不同的机制影响 NMDA 受体激活，但它们具有导致高度调节的 NMDA 受体激活紊乱的致病后果。由于序列变异、蛋白质终止变异和拷贝数变异而导致的 NMDA 受体激活紊乱通常是细胞特异性和区域选择性的。因此，可能需要长期给药的翻译治疗性 NMDA 受体激动剂干预措施必须具有特异性、选择性，并以生理方式促进 NMDA 受体激活（即模拟内源性释放的谷氨酸和甘氨酸/ D-丝氨酸在离散神经回路中对显著和相关的社会认知刺激的反应）。重要的是，缺失表达的基因敲除小鼠和有害基因杂合不足表达的小鼠通常可作为良好模型，以测试有前途的药物治疗策略的潜在疗效。该综述考虑了各种“疾病”基因的例子，它们对 NMDA 受体激活的致病影响，以及在可用的情况下，研究小鼠模型社交能力受损的结果，包括探索 NMDA 受体激动剂干预的“原理证明/概念验证”实验，以及开发有前途的正变构调节剂 (PAMs)，它们为开发 PAMs 和负变构调节剂 (NAMs) 的治疗干预目录提供支持和模型。可以想象，选择性 PAMs 和 NAMs 要么单独使用，要么根据患者的基因型联合使用，以增强和/或恢复 GluN2B 亚基和 GluN2A 亚基包含的 NMDA 受体激活介导的平衡紊乱。
