Postsynaptic receptors regulate presynaptic transmitter stability through transsynaptic bridges

Significance

Sites of presynaptic neurotransmitter release are tightly correlated with the postsynaptic expression of cognate neurotransmitter receptors. At the same time, many neurons express more than one neurotransmitter and their synaptic partners express more than one population of transmitter receptors. It is essential for information transfer at synapses that transmitters and receptors are matched. Failure to achieve a transmitter–receptor match would cause failure of synaptic transmission. Using pharmacological, immunocytochemical, neurophysiological, and molecular methods, we show that postsynaptic neurotransmitter receptors are necessary and sufficient to achieve the stabilization of their cognate neurotransmitter in the presynaptic neuron. This retrograde signal from different receptors is mediated by physical bridges of proteins involving synapse adhesion molecules. These transsynaptic bridges specify neurotransmitter identity.

Abstract

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 _A receptors) in muscle cells stabilizes an earlier, developmentally transient GABAergic motor neuron phenotype. Both AChR and GABA _A 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.