Molecular and functional architecture of striatal dopamine release sites
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Abstract
Despite the importance of dopamine for striatal circuit function, mechanistic understanding of dopamine transmission remains incomplete. We recently showed that dopamine secretion relies on the presynaptic scaffolding protein RIM, indicating that it occurs at active zone-like sites similar to classical synaptic vesicle exocytosis. Here, we establish using a systematic gene knockout approach that Munc13 and Liprin-α, active zone proteins for vesicle priming and release site organization, are important for dopamine secretion. Furthermore, RIM zinc finger and C 2 B domains, which bind to Munc13 and Liprin-α, respectively, are needed to restore dopamine release after RIM ablation. In contrast, and different from typical synapses, the active zone scaffolds RIM-BP and ELKS, and RIM domains that bind to them, are expendable. Hence, dopamine release necessitates priming and release site scaffolding by RIM, Munc13, and Liprin-α, but other active zone proteins are dispensable. Our work establishes that efficient release site architecture mediates fast dopamine exocytosis.
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The specificity of anti-Munc13-1 and anti-bMunc13-2 antibodies was confirmed using knock-out animals.
“The specificity of anti-Munc13-1 and anti-bMunc13-2 antibodies was confirmed using replicas of acute hippocampal slices prepared from Munc13-1cKO-Munc13-2/3(−/−) animals [110,111].”
From Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons (2024) · cites this paper as [111]
The STAR Methods (page unavailable) describe Munc13 knockout mice and anti-Munc13-1 antibodies used for Western blots, but do not report validating anti-Munc13-1 and anti-bMunc13-2 antibodies on replicas of acute hippocampal slices. Searches for antibody specificity, anti-bMunc13-2, and hippocampal-slice replicas found no passage addressing that validation. (LLM, conf=0.75)
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Self-citationSynapse and active zone assembly in the absence of presynaptic Ca2+ channels and Ca2+ entry
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Self-citationNeurexins cluster Ca2+ channels within the presynaptic active zone
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Liprin-α3 controls vesicle docking and exocytosis at the active zone of hippocampal synapses
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Self-citationRegional Heterogeneity of D2-Receptor Signaling in the Dorsal Striatum and Nucleus Accumbens
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The RAB3-RIM pathway is essential for the release of neuromodulators
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Self-citationSynaptotagmin-1 is the Ca2+ sensor for fast striatal dopamine release
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Self-citationTwo distinct secretory vesicle–priming steps in adrenal chromaffin cells
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Self-citationMunc13-Independent Vesicle Priming at Mouse Photoreceptor Ribbon Synapses
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Self-citationIdentification of a Munc13-sensitive step in chromaffin cell large dense-core vesicle exocytosis
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LAR receptor phospho-tyrosine phosphatases regulate NMDA-receptor responses
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RIM C2B Domains Target Presynaptic Active Zone Functions to PIP2-Containing Membranes
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Self-citationRIM-BP2 primes synaptic vesicles via recruitment of Munc13-1 at hippocampal mossy fiber synapses
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RIM is essential for stimulated but not spontaneous somatodendritic dopamine release in the midbrain
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Self-citationDopaminergic neurons establish a distinctive axonal arbor with a majority of non‐synaptic terminals
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Self-citationMunc18 and Munc13 regulate early neurite outgrowth
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Intact synapse structure and function after combined knockout of PTPδ, PTPσ, and LAR
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Self-citationAuthor response: LAR receptor phospho-tyrosine phosphatases regulate NMDA-receptor responses
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Self-citation
- Authors
- Banerjee, A., Imig, C., Balakrishnan, K., Kershberg, L., Lipstein, N., Uronen, R.-L., Wang, J., Cai, X., Benseler, F., Rhee, J. S., Cooper, B. H., Liu, C., Wojcik, S. M., Brose, N., & Kaeser, P. S.
- Affiliations
- Harvard University (US)
- Max Planck Institute of Experimental Medicine (DE)
- Corresponding author
- Kaeser, Pascal S.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2022-01
- Volume
- 110
- Issue
- 2
- Pages
- 248-265.e9
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC8859508
- OpenAlex
- W3214185212
- Cited by
- 58
- References
- 118
- Citations by year
- 2026: 15 · 2025: 10 · 2024: 10 · 2023: 10 · 2022: 9 · 2021: 4
- FWCI
- 4.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 383 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion)
- Funders
- DFG (EXC 2067/1-390729940)
- China Scholarship Council
- ERC
- NIH (F31NS105159, R01MH113349, R01NS103484)
- European Commission
- Massachusetts Institute of Technology
- Xi’an Jiaotong University
- Harvard University
- European Research Council (EXC 2067/1-390729940)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- dopamine release, striatum, RIM, Munc13, Liprin-α, active zone, synaptic vesicle exocytosis, vesicle priming, elk, gene knockout, dopamine signaling
- MeSH terms
- Corpus Striatum, Dopamine, Exocytosis, Synaptic Transmission, Synapses
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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