Abstract
Synaptic plasticity is believed to be the cellular basis for experience-dependent learning and memory. Although long-term depression (LTD), a form of synaptic plasticity, is caused by the activity-dependent reduction of cell surface α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors (AMPA receptors) at postsynaptic sites, its regulation by neuronal activity is not completely understood. In this study, we showed that the inhibition of toll-like receptor-9 (TLR9), an innate immune receptor, suppresses N-methyl-d-aspartate (NMDA)-induced reduction of cell surface AMPA receptors in cultured hippocampal neurons. We found that inhibition of TLR9 also blocked NMDA-induced activation of caspase-3, which plays an essential role in the induction of LTD. siRNA-based knockdown of TLR9 also suppressed the NMDA-induced reduction of cell surface AMPA receptors, although the scrambled RNA had no effect on the NMDA-induced trafficking of AMPA receptors. Overexpression of the siRNA-resistant form of TLR9 rescued the AMPA receptor trafficking abolished by siRNA. Furthermore, NMDA stimulation induced rapid mitochondrial morphological changes, mitophagy, and the binding of mitochondrial DNA (mtDNA) to TLR9. Treatment with dideoxycytidine and mitochondrial division inhibitor-1, which block mtDNA replication and mitophagy, respectively, inhibited NMDA-dependent AMPA receptor internalization. These results suggest that mitophagy induced by NMDA receptor activation releases mtDNA and activates TLR9, which plays an essential role in the trafficking of AMPA receptors during the induction of LTD.
Keywords:
AMPA receptor; caspase-3; endocytosis; ionotropic glutamate receptor; long-term depression; mitochondria; neuron; synaptic plasticity; toll-like receptor.