Postsynaptic receptors regulate presynaptic neurotransmitter stability

Stable matching of neurotransmitters with their receptors is fundamental to synapse function, to achieve reliable and robust communication in neural circuits. Presynaptic neurotransmitters regulate selection of postsynaptic transmitter receptors. However, whether postsynaptic receptors regulate selection of presynaptic transmitters is unknown. Here we show that blockade of postsynaptic acetylcholine receptors at the neuromuscular junction leads to loss of the cholinergic phenotype in motor neurons and stabilization of an earlier, developmentally transient glutamatergic phenotype. Exogenous postsynaptic expression of GABAA receptors leads to the stabilization of an earlier, developmentally transient GABAergic motor neuron phenotype. Both acetylcholine receptors and GABA receptors are linked to presynaptic neurons through trans-synaptic bridges. Knock-down of different components of these trans-synaptic bridges prevents stabilization of the cholinergic and GABAergic phenotypes. We conclude that this bidirectional communication enforces a match between transmitter and receptor and ensures the fidelity of synaptic transmission. Our findings suggest a role of dysfunctional transmitter receptors in neurological disorders that involve the loss of the presynaptic transmitter.