Sell_2024_bioRxiv__

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 (1-4) , yet glutamate clearly regulates glutamate receptor trafficking (5,6) and induces spine formation (7-11) . Using a culture system 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 NMDAR transport and surface expression as well as co-transport 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. Thus, like acetylcholine at the NMJ, 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.