Research ArticleAlcohol Addiction

Daily alcohol intake triggers aberrant synaptic pruning leading to synapse loss and anxiety-like behavior

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Science Signaling  22 Sep 2020:
Vol. 13, Issue 650, eaba5754
DOI: 10.1126/scisignal.aba5754

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Microglia binge on synapses

Alcohol abuse has detrimental cognitive and behavioral consequences. Binge drinking activates resident phagocytic immune cells in the brain called microglia in mice and is associated with anxiety in humans. Socodato et al. found that a binge drinking protocol in male mice induced microglia to selectively scavenge excitatory synapses between neurons in the prefrontal cortex. The loss of these connections did not cause neuronal death during the study but instead depressed neurotransmission and increased anxiety-like behaviors in the mice. These findings suggest that binge drinking induces anxiety by activating microglia that destroy neuronal connections.

Abstract

Alcohol abuse adversely affects the lives of millions of people worldwide. Deficits in synaptic transmission and in microglial function are commonly found in human alcohol abusers and in animal models of alcohol intoxication. Here, we found that a protocol simulating chronic binge drinking in male mice resulted in aberrant synaptic pruning and substantial loss of excitatory synapses in the prefrontal cortex, which resulted in increased anxiety-like behavior. Mechanistically, alcohol intake increased the engulfment capacity of microglia in a manner dependent on the kinase Src, the subsequent activation of the transcription factor NF-κB, and the consequent production of the proinflammatory cytokine TNF. Pharmacological blockade of Src activation or of TNF production in microglia, genetic ablation of Tnf, or conditional ablation of microglia attenuated aberrant synaptic pruning, thereby preventing the neuronal and behavioral effects of the alcohol. Our data suggest that aberrant pruning of excitatory synapses by microglia may disrupt synaptic transmission in response to alcohol abuse.

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