Deficiency in transmitter release triggers homeostatic transcriptional changes that increase presynaptic excitability.

Cypranowska, Caroline A; Feldthouse, Maya; Choi, Yoon Gi; Bakshinska, Dariya; Li, Rachel; Newman, Zachary L; Isacoff, Ehud Y · Proc Natl Acad Sci U S A · 2025

basic_science · Level V

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Abstract

Weakening of synaptic transmission at the <i>Drosophila</i> larval neuromuscular junction triggers two forms of homeostatic compensation, one that increases the probability of glutamate release per action potential (<i>P<sub>r</sub></i>) and another that increases motoneuron (MN) activity. We investigated the molecular changes in MNs that underlie the increase in MN activity. RNA sequencing (RNA-seq) analysis on MNs whose glutamate release is weakened by knockdown of components of the MN transmitter release machinery reveals a reduction in expression of a group of genes that encode potassium channels and their positive modulators. These results identify a mechanism of compensation for weakened synaptic transmission by MNs, which engages a transcriptional program in those cells to increase firing and, thereby, ensure sufficient locomotory drive.

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