Acute reorganization of postsynaptic GABAA receptors reveals the functional impact of molecular nanoarchitecture at inhibitory synapses
Samantha S. Olah, Dean J. Kareemo, William C. Buchta, Brooke L. Sinnen, Carley N. Miller, Hannah Actor-Engel, Sara E. Gookin, Christina S. Winborn, Mason S. Kleinjan, Kevin C. Crosby, Jason Aoto, Katharine R. Smith, Matthew J. Kennedy
Abstract
Neurotransmitter receptors partition into nanometer-scale subdomains within the postsynaptic membrane that are precisely aligned with presynaptic neurotransmitter release sites. While spatial coordination between pre- and postsynaptic elements is observed at both excitatory and inhibitory synapses, the functional significance of this molecular architecture has been challenging to evaluate experimentally. Here we utilized an optogenetic clustering approach to acutely alter the nanoscale organization of the postsynaptic inhibitory scaffold gephyrin while monitoring synaptic function. Gephyrin clustering rapidly enlarged postsynaptic area, laterally displacing GABA A receptors from their normally precise apposition with presynaptic active zones. Receptor displacement was accompanied by decreased synaptic GABA A receptor currents even though presynaptic release probability and the overall abundance and function of synaptic GABA A receptors remained unperturbed. Thus, acutely repositioning neurotransmitter receptors within the postsynaptic membrane profoundly influences synaptic efficacy, establishing the functional importance of precision pre-/postsynaptic molecular coordination at inhibitory synapses.