Overview

• University of Cologne researchers report that gephyrin forms elongated filaments that constitute the structural basis of inhibitory postsynaptic densities.
• Single-particle cryo-electron microscopy shows E-domain dimers connected by Z-shaped interfaces between SDII regions of adjacent dimers.
• Deleting SDII or introducing epilepsy-associated gephyrin variants prevented filament formation, in vitro phase separation, and receptor clustering in hippocampal neurons.
• The work challenges models that cast synaptic condensates as largely disordered, revealing an unexpectedly ordered molecular architecture.
• The peer-reviewed findings, published in Nature Communications, provide mechanistic insight that identifies early-stage targets for future neurological therapies.