Abstract
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.
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Acknowledgements
We would like to thank Drs Simon Richardson, Giulia Getty, Lauren Pecorino, and members of the Fivaz lab for critical reading of the manuscript.
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This work was funded by research grants to K-LL from the Ministry of Education, Singapore under its AcRF Tier 3 (MOE2017-T3-1-002) and research grants to MF from the Leverhulme Trust (RPG-2018-265) and from the Ministry of Education Singapore (MOE2013-T2-1-053).
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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by WT, BC, and MF under the supervision of K-LL The first draft of the manuscript was written by MF and all authors commented on previous version of the manuscript. All authors read and approved the final manuscript.
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Tang, W., Cory, B., Lim, KL. et al. The Mood Stabilizer Lithium Slows Down Synaptic Vesicle Cycling at Glutamatergic Synapses. Neuromol Med 25, 125–135 (2023). https://doi.org/10.1007/s12017-022-08729-8
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DOI: https://doi.org/10.1007/s12017-022-08729-8