Cited by 258Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchMemory and Neural Mechanisms

Synaptic scaffold evolution generated components of vertebrate cognitive complexity

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Nithianantharajah, Jess, Komiyama, Noboru H, McKechanie, Andrew, Johnstone, Mandy, Blackwood, Douglas H, Clair, David St, Emes, Richard D, van de Lagemaat, Louie N +3 more·2013·Nature Neuroscience

Abstract

The origins and evolution of higher cognitive functions, including complex forms of learning, attention and executive functions, are unknown. A potential mechanism driving the evolution of vertebrate cognition early in the vertebrate lineage (550 million years ago) was genome duplication and subsequent diversification of postsynaptic genes. Here we report, to our knowledge, the first genetic analysis of a vertebrate gene family in cognitive functions measured using computerized touchscreens. Comparison of mice carrying mutations in each of the four Dlg paralogs showed that simple associative learning required Dlg4, whereas Dlg2 and Dlg3 diversified to have opposing functions in complex cognitive processes. Exploiting the translational utility of touchscreens in humans and mice, testing Dlg2 mutations in both species showed that Dlg2's role in complex learning, cognitive flexibility and attention has been highly conserved over 100 million years. Dlg-family mutations underlie psychiatric disorders, suggesting that genome evolution expanded the complexity of vertebrate cognition at the cost of susceptibility to mental illness.

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Crossref · 10.1038/nn.3276

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  • 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 [7]

    The Discussion (page unavailable) describes Dlg scaffold proteins as part of synaptic signalling complexes and notes their association with NMDA receptors, supporting the postsynaptic-receptor portion. The paper does not say that these proteins organize presynaptic release sites, so that portion is unsupported. (LLM, conf=0.84)

    Experimental — accuracy not yet measured
  • 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 [7]

  • 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 [7]

  • 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 [7]

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Authors
Nithianantharajah, J., Komiyama, N. H., McKechanie, A., Johnstone, M., Blackwood, D. H., Clair, D. S., Emes, R. D., van de Lagemaat, L. N., Saksida, L. M., Bussey, T. J., & Grant, S. G. N.
Affiliations
  • University of Edinburgh (GB)
  • Wellcome Sanger Institute (GB)
  • Royal Edinburgh Hospital (GB)
  • University of Aberdeen (GB)
  • University of Nottingham (GB)
  • University of Cambridge (GB)
Corresponding author
Grant, Seth G N
Venue
Nature Neuroscience
Published
2012-12-02
Volume
16
Issue
1
Pages
16-24
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
OpenAlex
W1991426898
Cited by
251
References
54
Citations by year
2026: 11 · 2025: 4 · 2024: 15 · 2023: 8 · 2022: 14 · 2021: 16 · 2020: 27 · 2019: 18 · 2018: 28 · 2017: 29 · 2016: 19 · 2015: 29 · 2014: 18 · 2013: 13 · 2012: 2
FWCI
11.12
Type
journal article
Language
en
Open access
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Scholarship@Western (Western University) (submittedVersion)
Funders
  • Wellcome Trust (241995, 066717, 089703, 242167)
  • European Commission (242167, 241995)
  • Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
synaptic scaffolds, PSD-95, DLG3, associative learning, cognitive flexibility, attention, executive function, whole-genome duplication, functional diversification, mental illness
MeSH terms
SAP90-PSD95 Associated Proteins, Disks Large Homolog 4 Protein, Adult, Aged, Analysis of Variance, Animals, Association Learning, Attention, Choice Behavior, Chromosomes, Human, Pair 11, Cognition Disorders, Conditioning, Classical, Conditioning, Operant, Discrimination, Psychological, Biological Evolution, Extinction, Psychological, Female, Humans, Male, Membrane Proteins, Mice, Inbred C57BL, Mutation, Nerve Tissue Proteins, Neuropsychological Tests, Nuclear Proteins, Photic Stimulation, Reaction Time, Synapses, Touch, Transcription Factors, Conserved Sequence, Maze Learning, Mice, Guanylate Kinases

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