Chronic exposure of alcohol triggers microglia-mediated synaptic elimination inducing cognitive impairment

Background and aims: Long-term alcohol intake leads to cognitive impairment and dementia. The impairment of the cerebral cortex and limbic structures in alcoholics is associated with the loss of synapses instead of neurons. Synapse loss is considered to be an early and key feature of many neurodegenerative diseases, in which microglia-mediated synapse elimination is vital. However, the underlying mechanisms of synapse loss and cognitive impairment caused by long-term alcohol intake are still largely unknown. Methods: We investigated the relationship of synapse impairment, the microglial innate immune receptor--TREM2, and microglia-mediated synaptic elimination in long-term alcohol exposure. Results: We found that long-term alcohol exposure increased expression of TREM2, decreased expression of synaptic proteins and glutamate receptor subunits, reduced dendrite spine density, and impaired long-term potentiation (LTP) in the hippocampus. Minocycline reduced the amount of the postsynaptic marker PSD95 in microglia, attenuated dendrite spine density loss, and slow down the forgetting process of already-formed memory. Furthermore, we found that TREM2 participated in microglia-mediated synapse elimination in chronic alcohol exposure in vivo. Significantly fewer PSD95 were detectable in microglial phagolysosomes in TREM2 knockdown mice. Besides, TREM2 gene silencing ameliorated synapse loss, LTP impairment, and forgetting of remote memories. Conclusions: Our data suggests that TREM2 is associated with synaptic plasticity impairment and memory deficits, indicating microglia-mediated synaptic pruning might be the underlying mechanism involved in synapse loss and memory impairment induced by long-term alcohol intake. These findings provide new evidence for the receptor's participation in neurodegeneration diseases.

Automated summary

Long-term alcohol intake leads to synapse loss and cognitive impairment. Microglia-mediated synaptic elimination may play a key role in this mechanism.