Glutamate Signaling and Neuroligin/Neurexin Adhesion Play Opposing Roles That Are Mediated by Major Histocompatibility Complex I Molecules in Cortical Synapse Formation.

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 -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.