The DOI matches its Crossref record; 53 of the 54 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
An anatomically comprehensive atlas of the adult human brain transcriptome
Hawrylycz, M. J., Lein, E. S., Guillozet-Bongaarts, A. L., Shen, E. H., Ng, L., Miller, J. A., van de Lagemaat, L. N., Smith, K. A., Ebbert, A., Riley, Z. L., et al. (2012) · Nature · doi:10.1038/nature11405 · Cited by 3,083
Self-citationEvo-Devo and an Expanding Evolutionary Synthesis: A Genetic Theory of Morphological Evolution
Carroll, S. B. (2008) · Cell · doi:10.1016/j.cell.2008.06.030 · Cited by 2,067
Enhanced Perceptual Functioning in Autism: An Update, and Eight Principles of Autistic Perception
Mottron, L., Dawson, M., Soulières, I., Hubert, B., & Burack, J. (2006) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-005-0040-7 · Cited by 1,957
The Architecture of Cognitive Control in the Human Prefrontal Cortex
Koechlin, É., Ody, C., & Kouneiher, F. (2003) · Science · doi:10.1126/science.1088545 · Cited by 1,939
Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia
Walsh, T., McClellan, J. M., McCarthy, S. E., Addington, A. M., Pierce, S. B., Cooper, G. M., Nord, A. S., Kusenda, M., Malhotra, D., Bhandari, A., et al. (2008) · Science · doi:10.1126/science.1155174 · Cited by 1,800
Two Rounds of Whole Genome Duplication in the Ancestral Vertebrate
Dehal, P., & Boore, J. L. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030314 · Cited by 1,526
Proof and evolutionary analysis of ancient genome duplication in the yeast Saccharomyces cerevisiae
Kellis, M., Birren, B. W., & Lander, E. S. (2004) · Nature · doi:10.1038/nature02424 · Cited by 1,500
Rare chromosomal deletions and duplications increase risk of schizophrenia
The International Schizophrenia Consortium (2008) · Nature · doi:10.1038/nature07239 · Cited by 1,475
Polyploidy and genome evolution in plants
Adams, K. L., & Wendel, J. F. (2005) · Current Opinion in Plant Biology · doi:10.1016/j.pbi.2005.01.001 · Cited by 1,367
The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry
Robbins, T. (2002) · Psychopharmacology · doi:10.1007/s00213-002-1154-7 · Cited by 1,282
Flagged first, then by citations
1 of the 54 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
A polygenic burden of rare disruptive mutations in schizophrenia
Purcell, S. M., Moran, J. L., Fromer, M., Ruderfer, D., Solovieff, N., Roussos, P., O’Dushlaine, C., Chambert, K., Bergen, S. E., Kähler, A., et al. (2014) · Nature · doi:10.1038/nature12975 · Cited by 1,385
Self-citationThe origin and evolution of cell types
Arendt, D., Musser, J. M., Baker, C. V. H., Bergman, A., Cepko, C., Erwin, D. H., Pavlicev, M., Schlosser, G., Widder, S., Laubichler, M. D., et al. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.127 · Cited by 764
Common genetic variants influence human subcortical brain structures
Initiative, T. A. D. N., Hibar, D. P., The CHARGE Consortium, EPIGEN, IMAGEN, SYS, Stein, J. L., Renteria, M. E., Arias-Vasquez, A., Desrivières, S., et al. (2015) · Nature · doi:10.1038/nature14101 · Cited by 858
The octopus genome and the evolution of cephalopod neural and morphological novelties
Albertin, C. B., Simakov, O., Mitros, T., Wang, Z. Y., Pungor, J. R., Edsinger, E., Brenner, S., Ragsdale, C. W., & Rokhsar, D. S. (2015) · Nature · doi:10.1038/nature14668 · Cited by 628
Cortical Evolution: Judge the Brain by Its Cover
Geschwind, D. H., & Rakic, P. (2013) · Neuron · doi:10.1016/j.neuron.2013.10.045 · Cited by 519
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
