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The evolution of synaptic and cognitive capacity: Insights from the nervous system transcriptome of Aplysia

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Orvis, Joshua, Albertin, Caroline B., Shrestha, Pragya, Chen, Shuangshuang, Zheng, Melanie, Rodriguez, Cheyenne J., Tallon, Luke J., Mahurkar, Anup +7 more·2022·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2122301119PMC PMC9282427
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Abstract

The gastropod mollusk Aplysia is an important model for cellular and molecular neurobiological studies, particularly for investigations of molecular mechanisms of learning and memory. We developed an optimized assembly pipeline to generate an improved Aplysia nervous system transcriptome. This improved transcriptome enabled us to explore the evolution of cognitive capacity at the molecular level. Were there evolutionary expansions of neuronal genes between this relatively simple gastropod Aplysia (20,000 neurons) and Octopus (500 million neurons), the invertebrate with the most elaborate neuronal circuitry and greatest behavioral complexity? Are the tremendous advances in cognitive power in vertebrates explained by expansion of the synaptic proteome that resulted from multiple rounds of whole genome duplication in this clade? Overall, the complement of genes linked to neuronal function is similar between Octopus and Aplysia. As expected, a number of synaptic scaffold proteins have more isoforms in humans than in Aplysia or Octopus . However, several scaffold families present in mollusks and other protostomes are absent in vertebrates, including the Fifes, Lev10s, SOLs, and a NETO family. Thus, whereas vertebrates have more scaffold isoforms from select families, invertebrates have additional scaffold protein families not found in vertebrates. This analysis provides insights into the evolution of the synaptic proteome. Both synaptic proteins and synaptic plasticity evolved gradually, yet the last deuterostome-protostome common ancestor already possessed an elaborate suite of genes associated with synaptic function, and critical for synaptic plasticity.

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  • Increased cognitive power in sophisticated vertebrates is linked to an expansion of synaptic protein diversity, particularly scaffold proteins.

    “Evolutionary analyses suggest that the increased cognitive power in sophisticated vertebrates is linked to an expansion of synaptic protein diversity, particularly scaffold proteins, which mediate the precise organization of presynaptic release sites and postsynaptic receptors.”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [8]

    The paper describes the proposed link between cognitive capacity and expanded synaptic protein diversity, but its Abstract says its results challenge that hypothesis. In the Discussion (“Complexity of the Synaptic Proteome during Evolution”), comparisons involving zebrafish, humans, Octopus, and Aplysia lead the authors to conclude that greater nervous-system complexity is neither a direct consequence of, nor dependent on, greater synaptic protein diversity. The Abstract does support the sentence’s description of what scaffold proteins do. (LLM, conf=0.90)

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  • Dlg2 and Dlg3 have diversified to support complex cognitive functions across vertebrate evolution.

    “While some scaffold protein families found in invertebrates are absent in vertebrates, the latter generally possess more isoforms from families such as Dlg, where Dlg2 and Dlg3 have diversified to support complex cognitive functions across vertebrate evolution [7,8].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [8]

    The Results (Postsynaptic Scaffold Proteins; page unavailable) report more DLG-family gene isoforms in humans than in the mollusks examined. The Discussion (Complexity of the Synaptic Proteome during Evolution; page unavailable) says DLG-family members may contribute to different cognitive processes, but explicitly says there is not yet evidence that an individual DLG isoform has a unique role in learning-related plasticity. The paper does not establish the claimed cognitive purpose for Dlg2 and Dlg3 specifically. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Vertebrates generally possess more isoforms from scaffold protein families such as Dlg than invertebrates.

    “While some scaffold protein families found in invertebrates are absent in vertebrates, the latter generally possess more isoforms from families such as Dlg, where Dlg2 and Dlg3 have diversified to support complex cognitive functions across vertebrate evolution [7,8].”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [8]

  • Scaffold proteins mediate the precise organization of presynaptic release sites and postsynaptic receptors.

    “Evolutionary analyses suggest that the increased cognitive power in sophisticated vertebrates is linked to an expansion of synaptic protein diversity, particularly scaffold proteins, which mediate the precise organization of presynaptic release sites and postsynaptic receptors.”

    From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [8]

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Authors
Orvis, J., Albertin, C. B., Shrestha, P., Chen, S., Zheng, M., Rodriguez, C. J., Tallon, L. J., Mahurkar, A., Zimin, A. V., Kim, M., Liu, K., Kandel, E. R., Fraser, C. M., Sossin, W., & Abrams, T. W.
Affiliations
  • University of Maryland, Baltimore (US)
  • Marine Biological Laboratory (US)
  • Johns Hopkins University (US)
  • Circulomics (United States) (US)
  • Howard Hughes Medical Institute (US)
  • Montreal Neurological Institute and Hospital (CA)
Corresponding author
  • Kandel, Eric R.
  • Abrams, Thomas W.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2022-07-08
Volume
119
Issue
28
Pages
e2122301119-e2122301119
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2122301119
PMC
PMC9282427
OpenAlex
W4284975690
Cited by
26
References
82
Citations by year
2026: 9 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 3
FWCI
1.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Open Access Server of the Woods Hole Scientific Community (Woods Hole Scientific Community) (submittedVersion, cc-by-nc-nd)
Funders
  • Howard Hughes Medical Institute (n/a)
  • National Science Foundation (IOS-1255695)
  • HHS | National Institutes of Health (R01 MH 55880)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
Keywords
Aplysia, octopus, synaptic proteome, cognitive evolution, synaptic scaffold proteins, synaptic plasticity, whole-genome duplication, gene family expansion, molluscan nervous system, learning and memory
MeSH terms
Animals, Aplysia, Cognition, Biological Evolution, Neuronal Plasticity, Neurons, Synapses, Protein Isoforms, Proteome, Transcriptome

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