慢性社会ストレスによるシナプス構造変化とその分子機序の解析

抄録

Excessive or chronic social stress induces emotional and cognitive disturbances and precipitates mental illness. Altered neuronal morphology and functions in the medial prefrontal cortex (mPFC) underlie these behavioral abnormalities. However, its subcellular mechanisms remain elusive. Here we examined ultrastructural and multi-omics changes in the mPFC after social stress in mice. Social stress caused the loss of dendritic branches with morphological alterations of subcellular mitochondria and induced synaptic shrinkage selectively at the synapses with mitochondria. Multi-omics and functional analyses revealed that social stress deteriorated mitochondrial functions with altered mitochondrial proteome at synapses and dysregulated central metabolic pathways in the mPFC. Molecular biological and pharmacological manipulation targeting central metabolism and mitochondria attenuated the synaptic shrinkage and depression-related behaviors. These findings demonstrate that chronic social stress alters the central metabolism at mPFC synapses, leading to neuronal pathology and depression-related behaviors.