Postsynaptic receptors regulate presynaptic transmitter stability through trans-synaptic bridges

Abstract

Alteration of the electrical activity of the nervous system causes plasticity in neural circuits. Many of the changes occur at synapses. For example, neurotransmitter switching involves changes in the identity of presynaptic neurotransmitters and corresponding changes in postsynaptic transmitter receptors, thereby achieving a match between the transmitter and its cognate receptor. However, it is unknown whether changes in postsynaptic receptors can regulate presynaptic transmitters. Here we address this question at the developing neuromuscular junction. We find that blockade of endogenous postsynaptic acetylcholine receptors leads to loss of the cholinergic phenotype in motor neurons and the reappearance and stabilization of an earlier, developmentally transient glutamatergic phenotype. In addition, exogenous postsynaptic expression of GABAA receptors leads to the appearance and stabilization of an earlier, transient GABAergic motor neuron phenotype. Thus, acetylcholine receptors are necessary to stabilize acetylcholine as a transmitter, and GABAA receptors are sufficient to stabilize GABA as a transmitter. GARLH4 links the GABAA receptor to neuroligin, and Lrp4 links the acetylcholine receptor to dystroglycan through rapsyn and MUSK. Both neuroligin and dystroglycan bind to neurexin, which in turn binds to forms of the CASK transcription factor in motor neurons. Knock down of GARLH4 or Lrp4 postsynaptically or CASK presynaptically blocks stabilization of the GABAergic and cholinergic phenotypes. These results implicate transsynaptic bridges in establishing receptor-dependent stability of the cognate neurotransmitters. Our findings provide opportunities to investigate a role for dysfunctional transmitter receptors in neurological disorders that involve the loss of the presynaptic transmitter.

Generalized fear after acute stress is caused by change in neuronal cotransmitter identity

“…Transmitter switching may occur in a number of brain regions, such as the prefrontal cortex, where the GABA/glutamate ratio changes in response to stress (31)(32)(33). Transmitter switching in both the adult and the developing rodent nervous system has been linked to abnormal behavior triggered by stress (12,34,35), drugs (36)(37)(38), or infection (39), and linked to recovery when induced by epilepsy (40) or spinal cord injury (41).…”