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Cited by 54Neuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental DisordersNeurogenesis and neuroplasticity mechanisms

Molecular mechanisms of synaptogenesis

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Qi, Cai, Luo, Li-Da, Feng, Irena, Ma, Shaojie·2022·Frontiers in Synaptic Neuroscience
DOI 10.3389/fnsyn.2022.939793PMC PMC9513053
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Abstract

Synapses are the basic units for information processing and storage in the nervous system. It is only when the synaptic connection is established, that it becomes meaningful to discuss the structure and function of a circuit. In humans, our unparalleled cognitive abilities are correlated with an increase in the number of synapses. Additionally, genes involved in synaptogenesis are also frequently associated with neurological or psychiatric disorders, suggesting a relationship between synaptogenesis and brain physiology and pathology. Thus, understanding the molecular mechanisms of synaptogenesis is the key to the mystery of circuit assembly and neural computation. Furthermore, it would provide therapeutic insights for the treatment of neurological and psychiatric disorders. Multiple molecular events must be precisely coordinated to generate a synapse. To understand the molecular mechanisms underlying synaptogenesis, we need to know the molecular components of synapses, how these molecular components are held together, and how the molecular networks are refined in response to neural activity to generate new synapses. Thanks to the intensive investigations in this field, our understanding of the process of synaptogenesis has progressed significantly. Here, we will review the molecular mechanisms of synaptogenesis by going over the studies on the identification of molecular components in synapses and their functions in synaptogenesis, how cell adhesion molecules connect these synaptic molecules together, and how neural activity mobilizes these molecules to generate new synapses. Finally, we will summarize the human-specific regulatory mechanisms in synaptogenesis and results from human genetics studies on synaptogenesis and brain disorders.

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  • Synaptogenesis is initiated when axonal growth cones, extending from developing neurons, encounter their target cells and establish adhesive interactions.

    “Synaptogenesis, the formation of new synapses, is initiated when axonal growth cones, extending from developing neurons, encounter their target cells and establish adhesive interactions [49,73,74].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [49]

    The Introduction says synapse formation requires pre- and post-synaptic compartments to be aligned and connected by cell adhesion molecules. But the Concluding remarks and perspectives section says it remains unclear whether assembly starts with contact between those sites or with cytoskeletal organization. The paper therefore does not support the definite sequence in which growth cones encounter target cells and thereby initiate synaptogenesis. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Initial contact triggers a cascade of intracellular signaling events that lead to the recruitment and organization of presynaptic and postsynaptic components.

    “This initial contact triggers a cascade of intracellular signaling events that lead to the recruitment and organization of presynaptic and postsynaptic components.”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [49]

    The Introduction (page unavailable) describes assembly of pre- and postsynaptic molecules, and the assembly section reports that PSD95 accumulates after new contacts form. But the Concluding remarks (page unavailable) say it remains unclear whether synapse formation starts with contact or with prior cytoskeletal organization. The paper therefore does not establish that initial contact triggers the claimed intracellular signaling cascade. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • CAMs not only provide a mechanical link but also activate downstream pathways that remodel the cytoskeleton and organize the synaptic apparatus.

    “They not only provide a mechanical link but also activate downstream pathways that remodel the cytoskeleton and organize the synaptic apparatus [49,75].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [49]

    The section on cell adhesion molecules says they bridge pre- and postsynaptic components, interact with scaffold proteins, and can induce synapse formation (page unavailable). The sections on the cytoskeleton and activity-dependent synaptogenesis describe cytoskeletal remodeling and signaling, but do not establish that CAMs activate those downstream pathways. That causal part of the claim is not supported by our copy. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • SAP102 mediates the synaptic trafficking of both AMPA and NMDA receptors during early synaptogenesis.

    “Notably, SAP102 mediates the synaptic trafficking of both AMPA and NMDA receptors during early synaptogenesis [49], while PSD-95 assumes this function during synapse maturation, including the crucial replacement of NR2B-NMDARs with NR2A-NMDARs [40,50].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [49]

    In the 'Identification of synaptic components and their interactomes' section (page unavailable), the review names SAP102 as a discovered synaptic protein. Its References section (page unavailable) lists a study whose title says SAP102 interacts with NMDA receptor complexes, but our copy does not say SAP102 mediates trafficking of either NMDA or AMPA receptors during early synaptogenesis. Searched for SAP102 and early receptor trafficking. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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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

    “Notably, SAP102 mediates the synaptic trafficking of both AMPA and NMDA receptors during early synaptogenesis [49], while PSD-95 assumes this function during synapse maturation, including the crucial replacement of NR2B-NMDARs with NR2A-NMDARs [40,50].”

Authors
Qi, C., Luo, L.-D., Feng, I., & Ma, S.
Affiliations
  • Yale University (US)
  • Boston University (US)
Corresponding author
Qi, Cai
ORCID
Venue
Frontiers in Synaptic Neuroscience
Publisher
Frontiers Media SA
Published
2022-09-13
Volume
14
Pages
939793-939793
ISSN
1663-3563 (ISSN-L)
DOI
10.3389/fnsyn.2022.939793
PMC
PMC9513053
OpenAlex
W4295846911
Cited by
54
References
29
Citations by year
2026: 16 · 2025: 14 · 2024: 11 · 2023: 13
FWCI
1.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Synaptic Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
synaptogenesis, adhesion molecules, neuronal activity, neurological disorders, mental illness, circuit assembly

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