GluN3A is an atypical glycine-binding subunit of NMDA receptors (NMDARs) whose actions in the brain are mostly unknown. Here, we show that the expression of GluN3A subunits controls the excitability of mouse adult cortical and amygdalar circuits via an unusual signaling mechanism involving the formation of excitatory glycine GluN1/GluN3A receptors (eGlyRs) and their tonic activation by extracellular glycine. eGlyRs are mostly extrasynaptic and reside in specific neuronal populations, including the principal cells of the basolateral amygdala (BLA) and SST-positive interneurons (SST-INs) of the neocortex. In the BLA, tonic eGlyR currents are sensitive to fear-conditioning protocols, are subject to neuromodulation by the dopaminergic system, and control the stability of fear memories. In the neocortex, eGlyRs control the in vivo spiking of SST-INs and the behavior-dependent modulation of cortical activity. GluN3A-containing eGlyRs thus represent a novel and widespread signaling modality in the adult brain, with attributes that strikingly depart from those of conventional NMDARs.

GluN3A 是 NMDA 受体 (NMDAR) 的非典型甘氨酸结合亚基，其在大脑中的作用大多未知。在这里，我们表明 GluN3A 亚基的表达通过一种不寻常的信号传导机制控制小鼠成年皮质和杏仁核回路的兴奋性，这种信号传导机制涉及兴奋性甘氨酸 GluN1/GluN3A 受体 (eGlyRs) 的形成及其细胞外甘氨酸的强直激活。eGlyRs 大多是突触外的，存在于特定的神经元群中，包括新皮质的基底外侧杏仁核 (BLA) 和 SST 阳性中间神经元 (SST-INs) 的主要细胞。在 BLA 中，强直 eGlyR 电流对恐惧调节协议很敏感，受到多巴胺能系统的神经调节，并控制恐惧记忆的稳定性。在新皮质中，eGlyRs 控制SST-IN的体内尖峰和皮质活动的行为依赖性调节。因此，含有 GluN3A 的 eGlyRs 代表了成人大脑中一种新颖且广泛的信号传导方式，其属性与传统 NMDAR 的属性明显不同。