Gephyrin promotes autonomous assembly and synaptic localization of GABAergic postsynaptic components without presynaptic GABA release

• 成果类型: Article
• 署名作者: Carricaburu, Etta; Benner, Orion; Burlingham, Scott R.; Passos, Carolina Dos Santos; Hobaugh, Natalia; Karr, Charles H.; Chanda, Soham
• 署名单位: Colorado State University System; Colorado State University Fort Collins; University of Chicago; Colorado State University System; Colorado State University Fort Collins; Colorado State University System; Colorado State University Fort Collins
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11148
• DOI: 10.1073/pnas.2315100121
• 发表日期: 2024-06-25
• 关键词: gamma-aminobutyric-acid; inhibitory synapses; neuroligin 2; mental-retardation; direct binding; collybistin; absence; receptors; brain; synaptogenesis

摘要

Synapses containing gamma-aminobutyric acid (GABA) constitute the primary centers for inhibitory neurotransmission in our nervous system. It is unclear how these synaptic structures form and align their postsynaptic machineries with presynaptic terminals. Here, we monitored the cellular distribution of several GABAergic postsynaptic proteins in a purely glutamatergic neuronal culture derived from human stem cells, which virtually lacks any vesicular GABA release. We found that several GABAA receptor (GABAAR) subunits, postsynaptic scaffolds, and major cell- adhesion molecules can reliably coaggregate and colocalize at even GABA- deficient subsynaptic domains, but remain physically segregated from glutamatergic counterparts. Genetic deletions of both Gephyrin and a Gephyrin- associated guanosine di- or triphosphate (GDP/GTP) exchange factor Collybistin severely disrupted the coassembly of these postsynaptic compositions and their proper apposition with presynaptic inputs. Gephyrin-GABAAR clusters, developed in the absence of GABA transmission, could be subsequently activated and even potentiated by delayed supply of vesicular GABA. Thus, molecular organization of GABAergic postsynapses can initiate via a GABA- independent but Gephyrin- dependent intrinsic mechanism.