Wu Shiyun, Liu Zhongwan, Shao Robin, Zou Wenjin, Li Xiaoyue, Lu Weicong, Chen Jinyong, Yau Suk-Yu, Lin Kangguang
Department of Affective Disorder, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China.
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, People's Republic of China.
Bipolar Disord. 2025 Sep;27(6):461-471. doi: 10.1111/bdi.70056. Epub 2025 Sep 1.
Accumulative research indicates key roles of the peripheral inflammation system and hippocampal function in major mood disorders. The complement system modulates inflammatory function and is abnormal in mood disorders, but its precise neural pathway remains unclear. This study investigates the interrelations among complement component 3 (C3) levels, hippocampal function, and mood symptoms among offspring of bipolar disorder (BD) parents who carry familial risk of mood disorders.
We recruited unaffected BD offspring with (symptomatic offspring, SO, N = 31) or without (asymptomatic offspring, AO, N = 39) subthreshold symptoms, and matched healthy controls (HC, N = 41). Peripheral C3 levels were measured, and resting-state fMRI was conducted to assess hippocampal functional connectivity (FC). Spectral dynamic causal modeling (spDCM) was conducted to verify the directionality of the hippocampal FC.
The SO group exhibited significantly lower peripheral C3 levels (F = 23.651, p < 0.001) and reduced left hippocampus-left cerebellum FC (F = 8.541, p < 0.001) compared to both the AO and HC groups. Furthermore, the left hippocampus-left cerebellum FC partially mediated the relationship between C3 levels and depressive symptoms in the SO group (bootstrapping 95% CI = -4.1168 to -0.1569), but not in AO (bootstrapping 95% CI = -0.3479 to 0.1317) or HC (bootstrapping 95% CI = -0.3297 to 0.0885). The left hippocampus-left cerebellum FC was bidirectional in all 3 groups.
Our findings indicate a C3-hippocampus-depressive symptom pathway might underpin the particular high vulnerability of individuals with both familial and symptomatic risks of mood disorders. This evidence provides new neuroinflammatory markers and targets for early identification and intervention of these individuals.
累积研究表明外周炎症系统和海马功能在主要情绪障碍中起关键作用。补体系统调节炎症功能，且在情绪障碍中存在异常，但其确切的神经通路仍不清楚。本研究调查携带情绪障碍家族风险的双相情感障碍（BD）父母的后代中补体成分3（C3）水平、海马功能和情绪症状之间的相互关系。
我们招募了有（症状性后代，SO，N = 31）或无（无症状后代，AO，N = 39）阈下症状的未受影响的BD后代，以及匹配的健康对照（HC，N = 41）。测量外周C3水平，并进行静息态功能磁共振成像以评估海马功能连接性（FC）。进行频谱动态因果模型（spDCM）以验证海马FC的方向性。
与AO组和HC组相比，SO组的外周C3水平显著降低（F = 23.651，p < 0.001），左海马-左小脑FC降低（F = 8.541，p < 0.001）。此外，左海马-左小脑FC部分介导了SO组中C3水平与抑郁症状之间的关系（自抽样95% CI = -4.1168至-0.1569），但在AO组（自抽样95% CI = -0.3479至0.1317）或HC组（自抽样95% CI = -0.3297至0.0885）中未介导。左海马-左小脑FC在所有3组中都是双向的。
我们的研究结果表明，C3-海马-抑郁症状通路可能是情绪障碍家族风险和症状风险个体特别高易感性的基础。这一证据为这些个体的早期识别和干预提供了新的神经炎症标志物和靶点。
