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

Publisher: Society for Neuroscience Country of Publication: United States NLM ID: 8102140 Publication Model: Electronic Cited Medium: Internet ISSN: 1529-2401 (Electronic) Linking ISSN: 02706474 NLM ISO Abbreviation: J Neurosci Subsets: MEDLINE

Publication: Washington, DC : Society for Neuroscience
Original Publication: [Baltimore, Md.] : The Society, c1981-

Cell Adhesion Molecules, Neuronal*/metabolism ; Synapses*/metabolism ; Synapses*/physiology ; Glutamic Acid*/metabolism ; Cerebral Cortex*/metabolism ; Cerebral Cortex*/cytology; Animals ; Mice ; Rats ; Male ; Female ; Receptors, N-Methyl-D-Aspartate/metabolism ; Signal Transduction/physiology ; Cells, Cultured ; Rats, Sprague-Dawley ; Neurons/metabolism ; Neurons/physiology ; Neural Cell Adhesion Molecules/metabolism ; Mice, Inbred C57BL ; Nerve Tissue Proteins/metabolism ; Neuroligins ; Calcium-Binding Proteins

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.
Competing Interests: The authors declare no competing financial interests.
(Copyright © 2024 the authors.)

Update of: bioRxiv. 2024 Mar 07:2024.03.05.583626. doi: 10.1101/2024.03.05.583626. (PMID: 38496590)

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R01 EY013584 United States EY NEI NIH HHS; R01 NS060125 United States NS NINDS NIH HHS

Keywords: MHCI; homeostatic plasticity; neuroimmunology; neuroligin; synaptogenesis

0 (Cell Adhesion Molecules, Neuronal)
3KX376GY7L (Glutamic Acid)
0 (neuroligin 1)
0 (Receptors, N-Methyl-D-Aspartate)
0 (Nrxn1 protein, mouse)
0 (Neural Cell Adhesion Molecules)
0 (Nerve Tissue Proteins)
0 (Neuroligins)
0 (Calcium-Binding Proteins)

Date Created: 20241018 Date Completed: 20241204 Latest Revision: 20241208

20241209

PMC11622183

10.1523/JNEUROSCI.0797-24.2024

39424368