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Synaptic scaffold evolution generated components of vertebrate cognitive complexity
Open accessAbstract
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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“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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“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]
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“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]
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“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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Metadata
- 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
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2012-12-02
- Volume
- 16
- Issue
- 1
- Pages
- 16-24
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4131247
- 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
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- 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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