Induction of synapse formation by de novo neurotransmitter synthesis

Scott R. Burlingham, Nicole F. Wong, Lindsay Peterkin, Lily Lubow, Carolina Dos Santos Passos, Orion Benner, Michael Ghebrial, Thomas P. Cast, Matthew A. Xu-Friedman (), Thomas C. Südhof () and Soham Chanda ()
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Scott R. Burlingham: Colorado State University
Nicole F. Wong: State University of New York at Buffalo
Lindsay Peterkin: Colorado State University
Lily Lubow: Colorado State University
Carolina Dos Santos Passos: Colorado State University
Orion Benner: Colorado State University
Michael Ghebrial: California State University Fullerton
Thomas P. Cast: Colorado State University
Matthew A. Xu-Friedman: State University of New York at Buffalo
Thomas C. Südhof: Stanford University School of Medicine
Soham Chanda: Colorado State University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract A vital question in neuroscience is how neurons align their postsynaptic structures with presynaptic release sites. Although synaptic adhesion proteins are known to contribute in this process, the role of neurotransmitters remains unclear. Here we inquire whether de novo biosynthesis and vesicular release of a noncanonical transmitter can facilitate the assembly of its corresponding postsynapses. We demonstrate that, in both stem cell-derived human neurons as well as in vivo mouse neurons of purely glutamatergic identity, ectopic expression of GABA-synthesis enzymes and vesicular transporters is sufficient to both produce GABA from ambient glutamate and transmit it from presynaptic terminals. This enables efficient accumulation and consistent activation of postsynaptic GABAA receptors, and generates fully functional GABAergic synapses that operate in parallel but independently of their glutamatergic counterparts. These findings suggest that presynaptic release of a neurotransmitter itself can signal the organization of relevant postsynaptic apparatus, which could be directly modified to reprogram the synapse identity of neurons.

Date: 2022
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DOI: 10.1038/s41467-022-30756-z

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