The mood stabilizer lithium slows down synaptic vesicle cycling at glutamatergic synapses
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 glutam...
| Main Authors: | , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/170540 |
| _version_ | 1826125240567070720 |
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| author | Tang, Willcyn Cory, Bradley Lim, Kah-Leong Fivaz, Marc |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Tang, Willcyn Cory, Bradley Lim, Kah-Leong Fivaz, Marc |
| author_sort | Tang, Willcyn |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T06:33:29Z |
| format | Journal Article |
| id | ntu-10356/170540 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:33:29Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1705402023-09-19T02:05:40Z The mood stabilizer lithium slows down synaptic vesicle cycling at glutamatergic synapses Tang, Willcyn Cory, Bradley Lim, Kah-Leong Fivaz, Marc Lee Kong Chian School of Medicine (LKCMedicine) National Neuroscience Institute Science::Medicine Bipolar Disorder Synaptic Vesicle Cycle 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. Ministry of Education (MOE) 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). 2023-09-19T02:05:40Z 2023-09-19T02:05:40Z 2023 Journal Article Tang, W., Cory, B., Lim, K. & Fivaz, M. (2023). The mood stabilizer lithium slows down synaptic vesicle cycling at glutamatergic synapses. Neuromolecular Medicine, 25(1), 125-135. https://dx.doi.org/10.1007/s12017-022-08729-8 1535-1084 https://hdl.handle.net/10356/170540 10.1007/s12017-022-08729-8 36436129 2-s2.0-85142651233 1 25 125 135 en MOE2017-T3-1–002 Neuromolecular Medicine © 2022 The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. All rights reserved. |
| spellingShingle | Science::Medicine Bipolar Disorder Synaptic Vesicle Cycle Tang, Willcyn Cory, Bradley Lim, Kah-Leong Fivaz, Marc The mood stabilizer lithium slows down synaptic vesicle cycling at glutamatergic synapses |
| title | The mood stabilizer lithium slows down synaptic vesicle cycling at glutamatergic synapses |
| title_full | The mood stabilizer lithium slows down synaptic vesicle cycling at glutamatergic synapses |
| title_fullStr | The mood stabilizer lithium slows down synaptic vesicle cycling at glutamatergic synapses |
| title_full_unstemmed | The mood stabilizer lithium slows down synaptic vesicle cycling at glutamatergic synapses |
| title_short | The mood stabilizer lithium slows down synaptic vesicle cycling at glutamatergic synapses |
| title_sort | mood stabilizer lithium slows down synaptic vesicle cycling at glutamatergic synapses |
| topic | Science::Medicine Bipolar Disorder Synaptic Vesicle Cycle |
| url | https://hdl.handle.net/10356/170540 |
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