Lithium is a mood stabilizer broadly used to prevent and treat symptoms of mania and depression in people with bipolar disorder (BD). Little is known, however, about its mode of action. Here, we analyzed the impact of lithium on synaptic vesicle (SV) cycling at presynaptic terminals releasing glutamate, a neurotransmitter previously implicated in BD and other neuropsychiatric conditions. We used the pHluorin-based synaptic tracer vGpH and a fully automated image processing pipeline to quantify the effect of lithium on both SV exocytosis and endocytosis in hippocampal neurons. We found that lithium selectively reduces SV exocytic rates during electrical stimulation, and markedly slows down SV recycling post-stimulation. Analysis of single-bouton responses revealed the existence of functionally distinct excitatory synapses with varying sensitivity to lithium—some terminals show responses similar to untreated cells, while others are markedly impaired in their ability to recycle SVs. While the cause of this heterogeneity is unclear, these data indicate that lithium interacts with the SV machinery and influences glutamate release in a large fraction of excitatory synapses. Together, our findings show that lithium down modulates SV cycling, an effect consistent with clinical reports indicating hyperactivation of glutamate neurotransmission in BD.

锂是一种情绪稳定剂，广泛用于预防和治疗双相情感障碍 (BD) 患者的躁狂和抑郁症状。然而，对其作用方式知之甚少。在这里，我们分析了锂对突触前末端突触小泡 (SV) 循环释放谷氨酸的影响，谷氨酸是一种先前与 BD 和其他神经精神疾病有关的神经递质。我们使用基于 pHluorin 的突触示踪剂 vGpH 和全自动图像处理管道来量化锂对海马神经元 SV 胞吐和胞吞的影响。我们发现锂在电刺激期间选择性地降低 SV 胞吐率，并显着减慢刺激后 SV 的再循环。对单次反应的分析揭示了功能不同的兴奋性突触的存在，这些突触对锂具有不同的敏感性——一些终端显示出与未处理细胞相似的反应，而其他终端在回收 SV 的能力方面明显受损。虽然这种异质性的原因尚不清楚，但这些数据表明锂与 SV 机制相互作用并影响大部分兴奋性突触中的谷氨酸释放。总之，我们的研究结果表明，锂向下调节 SV 循环，这种效果与临床报告一致，表明 BD 中谷氨酸神经传递的过度激活。这些数据表明锂与 SV 机制相互作用并影响大部分兴奋性突触中的谷氨酸释放。总之，我们的研究结果表明，锂向下调节 SV 循环，这种效果与临床报告一致，表明 BD 中谷氨酸神经传递的过度激活。这些数据表明锂与 SV 机制相互作用并影响大部分兴奋性突触中的谷氨酸释放。总之，我们的研究结果表明，锂向下调节 SV 循环，这种效果与临床报告一致，表明 BD 中谷氨酸神经传递的过度激活。