Although neurons release neurotransmitter before contact, the role for this release in synapse formation remains unclear. Cortical synapses do not require synaptic vesicle release for formation (Verhage et al., 2000; Sando et al., 2017; Sigler et al., 2017; Held et al., 2020), yet glutamate clearly regulates glutamate receptor trafficking (Roche et al., 2001; Nong et al., 2004) and induces spine formation (Engert and Bonhoeffer, 1999; Maletic-Savatic et al., 1999; Toni et al., 1999; Kwon and Sabatini, 2011; Oh et al., 2016). Using rat and murine culture systems to dissect molecular mechanisms, we found that glutamate rapidly decreases synapse density specifically in young cortical neurons in a local and calcium-dependent manner through decreasing N-methyl-d-aspartate receptor (NMDAR) transport and surface expression as well as cotransport with neuroligin (NL1). Adhesion between NL1 and neurexin 1 protects against this glutamate-induced synapse loss. Major histocompatibility I (MHCI) molecules are required for the effects of glutamate in causing synapse loss through negatively regulating NL1 levels in both sexes. Thus, like acetylcholine at the neuromuscular junction, glutamate acts as a dispersal signal for NMDARs and causes rapid synapse loss unless opposed by NL1-mediated trans-synaptic adhesion. Together, glutamate, MHCI, and NL1 mediate a novel form of homeostatic plasticity in young neurons that induces rapid changes in NMDARs to regulate when and where nascent glutamatergic synapses are formed.

尽管神经元在接触前会释放神经递质，但这种释放在突触形成中的作用仍不清楚。皮质突触不需要突触小泡释放即可形成（Verhage等人，2000 年;Sando等人，2017 年;Sigler等人，2017 年;Held等人，2020 年），但谷氨酸显然调节谷氨酸受体的运输（Roche 等人，2001 年;Nong et al.， 2004） 并诱导脊柱形成 （Engert and Bonhoeffer， 1999;Maletic-Savatic et al.， 1999;Toni 等人，1999 年;Kwon 和 Sabatini，2011 年;Oh et al.， 2016）。使用大鼠和小鼠培养系统剖析分子机制，我们发现谷氨酸通过减少 N-甲基-d-天冬氨酸受体 （NMDAR） 转运和表面表达以及与神经连接蛋白 （NL1） 的共转运，以局部和钙依赖性方式迅速降低年轻皮层神经元中的突触密度。NL1 和 neurexin 1 之间的粘附可防止这种谷氨酸诱导的突触丢失。主要组织相容性 I （MHCI） 分子是谷氨酸通过负向调节两性 NL1 水平导致突触丢失的作用所必需的。因此，与神经肌肉接头处的乙酰胆碱一样，谷氨酸充当 NMDAR 的分散信号，除非受到 NL1 介导的跨突触粘附的反对，否则会导致突触快速丢失。谷氨酸、MHCI 和 NL1 共同介导年轻神经元中一种新型的稳态可塑性，诱导 NMDAR 的快速变化，以调节新生谷氨酸能突触的形成时间和位置。