<p>Adequate evidence has shown that gut microbial dysbiosis is an emerging disease phenotype of bipolar disorder (BD), and is closely related to clinical symptoms of this intractable disease. However, how gut microbiota affects the nervous system in BD remains largely unclear. In this study, we constructed a BD depression-like mouse model via fecal microbiota transplantation, and explored the changes of synaptic plasticity and connectivity in the medial prefrontal cortex (mPFC) of BD mice. We found that bipolar depression-like mice presented with a decrease in the density of dendritic spines in medial prefrontal neurons, and “Translation at postsynapse” as a key contributor to the changes in synaptic plasticity. In addition, analysis of synaptic connectivity in the mPFC revealed that compared to control mice, less connections were observed between ventral tegmental area and mPFC glutamate neurons and dopamine response was decreased in BD mice. These findings suggest that gut microbiota from BD depression patients induces the development of bipolar depression possibly by modulating aberrant synaptic connectivity and dopamine transmission in the VTA-mPFC pathway, which sheds light on the microbiota-gut-brain mechanisms underlying BD.</p>