Toll-like receptor signaling modulates AMPA receptor trafficking in homeostatic synaptic downscaling

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 GABA_A 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.