Toll-like receptor signaling modulates AMPA receptor trafficking in homeostatic synaptic downscaling
- 1Department of Engineering Science, Graduate School of Informatics and Engineering, The University of Electro-Communications, Tokyo, 182-8585, Japan
Abstract
Homeostatic synaptic downscaling is a compensatory form of synaptic plasticity that stabilizes neuronal activity in response to sustained synaptic potentiation. Here, we investigated the involvement of Toll-like receptor (TLR) signaling in synaptic downscaling induced by bicuculline, a GABAA receptor antagonist. In cultured hippocampal neurons, bicuculline altered mitochondrial morphology and reduced the colocalization of TLR9 with mitochondrial DNA, an endogenous TLR9 ligand. Pharmacological inhibition of TLR9 mimicked bicuculline-induced reductions in surface expression of the AMPA receptor subunit GluA1 (sGluA1), and co-application of bicuculline and TLR9 inhibitors produced no additive effect, suggesting a shared pathway. Inhibition of SARM1, a downstream effector of TLR9, prevented bicuculline-induced sGluA1 reduction. Bicuculline also upregulated another upstream effector of SARM1, TLR7, which is negatively regulated by TLR9. TLR7 inhibition blocked, whereas TLR7 activation mimicked, bicuculline-induced decreases in sGluA1. These findings indicate that the shift from TLR9 to TLR7 signaling contributes to homeostatic synaptic downscaling.
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BibTeX
@article{koga2026tolllike,
title = {{Toll-like receptor signaling modulates AMPA receptor trafficking in homeostatic synaptic downscaling}},
author = {Akira Koga and Shuhei Kishi and Shinji Matsuda},
journal = {The journal of physiological sciences : JPS},
year = {2026},
month = oct,
doi = {10.1016/j.jphyss.2026.100112},
url = {https://europepmc.org/article/PMC/PMC13718798},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Toll-like receptor signaling modulates AMPA receptor trafficking in homeostatic synaptic downscaling
AU - Akira Koga
AU - Shuhei Kishi
AU - Shinji Matsuda
PY - 2026
DA - 2026/10/19
JO - The journal of physiological sciences : JPS
DO - 10.1016/j.jphyss.2026.100112
UR - https://europepmc.org/article/PMC/PMC13718798
AB - Homeostatic synaptic downscaling is a compensatory form of synaptic plasticity that stabilizes neuronal activity in response to sustained synaptic potentiation. Here, we investigated the involvement of Toll-like receptor (TLR) signaling in synaptic downscaling induced by bicuculline, a GABAA receptor antagonist. In cultured hippocampal neurons, bicuculline altered mitochondrial morphology and reduced the colocalization of TLR9 with mitochondrial DNA, an endogenous TLR9 ligand. Pharmacological inhibition of TLR9 mimicked bicuculline-induced reductions in surface expression of the AMPA receptor subunit GluA1 (sGluA1), and co-application of bicuculline and TLR9 inhibitors produced no additive effect, suggesting a shared pathway. Inhibition of SARM1, a downstream effector of TLR9, prevented bicuculline-induced sGluA1 reduction. Bicuculline also upregulated another upstream effector of SARM1, TLR7, which is negatively regulated by TLR9. TLR7 inhibition blocked, whereas TLR7 activation mimicked, bicuculline-induced decreases in sGluA1. These findings indicate that the shift from TLR9 to TLR7 signaling contributes to homeostatic synaptic downscaling.
SN - 1880-6546
SN - 1880-6562
ER -