Understanding the molecular diversity of synapses
Abstract
Synapses are composed of thousands of proteins, providing the potential for extensive molecular diversity to shape synapse type-specific functional specializations. In this Review, we explore the landscape of synaptic diversity and describe the mechanisms that expand the molecular complexity of synapses, from the genotype to the regulation of gene expression to the production of specific proteoforms and the formation of localized protein complexes. We emphasize the importance of examining every molecular layer and adopting a systems perspective to understand how these interconnected mechanisms shape the diverse functional and structural properties of synapses. We explore current frameworks for classifying synapses and methodologies for investigating different synapse types at varying scales, from synapse-type-specific proteomics to advanced imaging techniques with single-synapse resolution. We highlight the potential of synapse-type-specific approaches for integrating molecular data with cellular functions, circuit organization and organismal phenotypes to enable a more holistic exploration of neuronal phenomena across different scales.
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The unique properties of individual synapses are regulated through a continuous interplay of bidirectional signals exchanged between the presynaptic and postsynaptic compartments.
“The unique properties of individual synapses are regulated through a continuous interplay of bidirectional signals exchanged between the presynaptic and postsynaptic compartments [3,4].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [4]
The complex architecture of a synapse, characterized by its asymmetric organization, enables unidirectional signal propagation from the presynaptic terminal to the postsynaptic neuron.
“The complex architecture of a synapse, characterized by its asymmetric organization, enables unidirectional signal propagation from the presynaptic terminal to the postsynaptic neuron [2,3,4].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [4]
The molecular landscape of a synapse is complex, comprising thousands of distinct proteins that collectively dictate its functional specializations.
“The molecular landscape of a synapse is complex, comprising thousands of distinct proteins that collectively dictate its functional specializations [4].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [4]
The diversity observed in the properties of synapses cannot be fully predicted solely from their ultrastructure or anatomical location, highlighting the influence of their molecular composition.
“The diversity observed in the properties of synapses cannot be fully predicted solely from their ultrastructure or anatomical location, highlighting the influence of their molecular composition [1,4].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [4]
Munc13 is essential for both fast and modulatory release; its membrane-binding C2C domain is specifically crucial for neuropeptide secretion from large dense-core vesicles (DCVs), unlike the redundant C2B domain in small synaptic vesicle (SV) exocytosis.
“Munc13 is essential for both fast and modulatory release; however, its membrane-binding C2C domain is specifically crucial for neuropeptide secretion from large dense-core vesicles (DCVs), unlike the redundant C2B domain in small synaptic vesicle (SV) exocytosis [4,21].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [4]
Synapse removal is often initiated by the disengagement of SAM complexes and the cessation of their bidirectional signaling, which secondarily recruits microglia for phagocytic pruning, especially when the synaptic barcode fails to validate the connection during activity-dependent competition.
“Regarding elimination, synapse removal is often initiated by the disengagement of these SAM complexes and the cessation of their bidirectional signaling, which secondarily recruits microglia for phagocytic pruning, especially when the ‘synaptic barcode’ fails to validate the connection during activity-dependent competition [1,4,12].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [4]
The synaptome is built from the hierarchical expression and assembly of proteins into complexes and supercomplexes.
“The “synaptome,” which describes the diversity of synapses and their anatomical distribution, is built from the hierarchical expression and assembly of proteins into complexes and supercomplexes [4,10].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [4]
The extensive molecular repertoire of a synapse provides the potential for an almost unlimited number of synapse types, each with unique functional properties.
“This extensive molecular repertoire provides the potential for an almost unlimited number of synapse types, each with unique functional properties [4].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [4]
The vertebrate nervous system exhibits extensive synaptic diversity organized into a synaptome.
“The vertebrate nervous system exhibits extensive synaptic diversity, organized into a ‘synaptome’ where functional specialization is driven by the quantitative abundance of shared components rather than the presence of unique proteins [4].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [4]
Functional specialization of synapses is driven by the quantitative abundance of shared components rather than the presence of unique proteins.
“The vertebrate nervous system exhibits extensive synaptic diversity, organized into a ‘synaptome’ where functional specialization is driven by the quantitative abundance of shared components rather than the presence of unique proteins [4].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [4]
The proteome of a single synapse is complex, comprising thousands of distinct proteins.
“The proteome of a single synapse is complex, comprising thousands of distinct proteins.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [4]
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Molecular Physiology of the Neuronal Synapse
Ramírez-Expósito, M. J., Cueto-Ureña, C., & Martínez-Martos, J. M. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48010088 · Cited by 6 · see citing works
- Authors
- van Oostrum, M., & Schuman, E. M.
- Affiliations
- Max Planck Institute for Brain Research (DE)
- Corresponding author
- Schuman, Erin M.
- Venue
- Nature Reviews Neuroscience
- Published
- 2024-12-05
- Volume
- 26
- Issue
- 2
- Pages
- 65-81
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- OpenAlex
- W4405089709
- Cited by
- 49
- References
- 42
- Citations by year
- 2026: 38 · 2025: 10 · 2024: 1
- FWCI
- 3.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature reviews. Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- synaptic diversity, synaptic proteome, proteoforms, gene expression regulation, protein complexes, synaptic function, neural circuits
- MeSH terms
- Animals, Humans, Neurons, Synapses, Proteomics
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