Postsynaptic receptors regulate presynaptic transmitter stability through transsynaptic bridges

• Published in: Proceedings of the National Academy of Sciences - PNAS 2024-04, Vol.121 (15), p.e2318041121
• Main Authors: Godavarthi, Swetha K, Hiramoto, Masaki, Ignatyev, Yuri, Levin, Jacqueline B, Li, Hui-Quan, Pratelli, Marta, Borchardt, Jennifer, Czajkowski, Cynthia, Borodinsky, Laura N, Sweeney, Lora, Cline, Hollis T, Spitzer, Nicholas C
• Format: Article
• Language: English
• Subjects: Cholinergic Agents; Cholinergics; Circuit reliability; gamma-Aminobutyric Acid - metabolism; Genotype & phenotype; Glutamatergic transmission; Motor neurons; Motor Neurons - metabolism; Neural networks; Neurological diseases; Neurons; Neurotransmitter Agents - metabolism; Neurotransmitters; Phenotypes; Receptor mechanisms; Receptors; Receptors, Cholinergic - metabolism; Receptors, GABA-A - metabolism; Receptors, Presynaptic; Stabilization; Synapses - metabolism; Synaptic transmission; Synaptic Transmission - physiology; Transmitters; γ-Aminobutyric acid; γ-Aminobutyric acid A receptors
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2318041121

Stable matching of neurotransmitters with their receptors is fundamental to synapse function and reliable communication in neural circuits. Presynaptic neurotransmitters regulate the stabilization of postsynaptic transmitter receptors. Whether postsynaptic receptors regulate stabilization of presynaptic transmitters has received less attention. Here, we show that blockade of endogenous postsynaptic acetylcholine receptors (AChR) at the neuromuscular junction destabilizes the cholinergic phenotype in motor neurons and stabilizes an earlier, developmentally transient glutamatergic phenotype. Further, expression of exogenous postsynaptic gamma-aminobutyric acid type A receptors (GABA receptors) in muscle cells stabilizes an earlier, developmentally transient GABAergic motor neuron phenotype. Both AChR and GABA receptors are linked to presynaptic neurons through transsynaptic bridges. Knockdown of specific components of these transsynaptic bridges prevents stabilization of the cholinergic or GABAergic phenotypes. Bidirectional communication can enforce a match between transmitter and receptor and ensure the fidelity of synaptic transmission. Our findings suggest a potential role of dysfunctional transmitter receptors in neurological disorders that involve the loss of the presynaptic transmitter.