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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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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
Turning a hobby into a job: How duplicated genes find new functions
Conant, G. C., & Wolfe, K. H. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2482 · Cited by 1,281
Migaud, M., Charlesworth, P., Dempster, M., Webster, L. C., Watabe, A. M., Makhinson, M., He, Y., Ramsay, M. F., Morris, R. G. M., Morrison, J. H., et al. (1998) · Nature · doi:10.1038/24790 · Cited by 1,160
Self-citationThe evolutionary significance of ancient genome duplications
Van de Peer, Y., Maere, S., & Meyer, A. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2600 · Cited by 1,129
Kirov, G., Pocklington, A. J., Holmans, P., Ivanov, D., Ikeda, M., Ruderfer, D., Moran, J., Chambert, K., Toncheva, D., Georgieva, L., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.154 · Cited by 844
Self-citationStrong association of de novo copy number mutations with sporadic schizophrenia
Xu, B., Roos, J. L., Levy, S., van Rensburg, E. J., Gogos, J. A., & Karayiorgou, M. (2008) · Nature Genetics · doi:10.1038/ng.162 · Cited by 813
Chudasama, Y., & Robbins, T. W. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-25-08771.2003 · Cited by 543
The Oxford Companion to the Mind
Gregory, R. L. (1989) · International Clinical Psychopharmacology · doi:10.1097/00004850-198901000-00013 · Cited by 532
Characterization of the proteome, diseases and evolution of the human postsynaptic density
Bayés, À., van de Lagemaat, L. N., Collins, M. O., Croning, M. D. R., Whittle, I. R., Choudhary, J. S., & Grant, S. G. N. (2011) · Nature Neuroscience · doi:10.1038/nn.2719 · Cited by 499
Self-citationWoods, D. F., Hough, C., Peel, D., Callaini, G., & Bryant, P. J. (1996) · The Journal of cell biology · doi:10.1083/jcb.134.6.1469 · Cited by 417
Waltz, J. A., & Gold, J. M. (2007) · Schizophrenia Research · doi:10.1016/j.schres.2007.03.010 · Cited by 331
The Construct of Attention in Schizophrenia
Luck, S. J., & Gold, J. M. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.02.014 · Cited by 326
Bussey, T. J., Muir, J. L., Everitt, B. J., & Robbins, T. W. (1997) · Behavioral Neuroscience · doi:10.1037//0735-7044.111.5.920 · Cited by 311
Self-citationBussey, T. J., Holmes, A., Lyon, L., Mar, A. C., McAllister, K. A. L., Nithianantharajah, J., Oomen, C. A., & Saksida, L. M. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.04.011 · Cited by 299
Self-citationGene Duplication: A Drive for Phenotypic Diversity and Cause of Human Disease
Conrad, B., & Antonarakis, S. E. (2007) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.8.021307.110233 · Cited by 270
Fernández, E., Collins, M. O., Uren, R. T., Kopanitsa, M. V., Komiyama, N. H., Croning, M. D. R., Zografos, L., Armstrong, J. D., Choudhary, J. S., & Grant, S. G. N. (2009) · Molecular Systems Biology · doi:10.1038/msb.2009.27 · Cited by 270
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Konopka, G., Friedrich, T., Davis‐Turak, J., Winden, K. D., Oldham, M. C., Gao, F., Chen, L., Wang, G.-Z., Luo, R., Preuss, T. M., et al. (2012) · Neuron · doi:10.1016/j.neuron.2012.05.034 · Cited by 268
Leeson, V. C., Robbins, T. W., Matheson, E., Hutton, S. B., Ron, M. A., Barnes, T. R. E., & Joyce, E. M. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.05.016 · Cited by 219
Bayés, À., Collins, M. O., Croning, M. D. R., van de Lagemaat, L. N., Choudhary, J. S., & Grant, S. G. N. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046683 · Cited by 216
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Emes, R. D., Pocklington, A., Anderson, C. N. G., Bayés, À., Collins, M., Vickers, C., Croning, M., Malik, B., Choudhary, J., Armstrong, J., et al. (2008) · Nature Neuroscience · doi:10.1038/nn.2135 · Cited by 202
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Assessing cognitive function in clinical trials of schizophrenia
Barnett, J. H., Robbins, T. W., Leeson, V. C., Sahakian, B. J., Joyce, E. M., & Blackwell, A. D. (2010) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2010.01.012 · Cited by 178
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Tarpey, P., Parnau, J., Blow, M., Woffendin, H., Bignell, G., Cox, C., Cox, J., Davies, H., Edkins, S., Holden, S., et al. (2004) · The American Journal of Human Genetics · doi:10.1086/422703 · Cited by 176
Carlisle, H. J., Fink, A. E., Grant, S. G. N., & O’Dell, T. J. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.163469 · Cited by 172
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Moore, B. R. (2004) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1017/s1464793103006225 · Cited by 164
Bossinger, O., Klebes, A., Segbert, C., Theres, C., & Knust, E. (2001) · Developmental Biology · doi:10.1006/dbio.2000.0113 · Cited by 161
Impaired Attention in the 3xTgAD Mouse Model of Alzheimer's Disease: Rescue by Donepezil (Aricept)
Romberg, C., Mattson, M. P., Mughal, M. R., Bussey, T. J., & Saksida, L. M. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.5242-10.2011 · Cited by 160
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Talpos, J. C., Winters, B. D., Dias, R. S., Saksida, L. M., & Bussey, T. J. (2009) · Psychopharmacology · doi:10.1007/s00213-009-1526-3 · Cited by 122
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Suls, A., Claeys, K. G., Goossens, D., Harding, B., van Luijk, R., Scheers, S., Deprez, L., Audenaert, D., Dyck, T. V., Beeckmans, S., et al. (2006) · Human Mutation · doi:10.1002/humu.20350 · Cited by 114
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Ryan, T. J., Kopanitsa, M. V., Indersmitten, T., Nithianantharajah, J., Afinowi, N. O., Pettit, C., Stanford, L. E., Sprengel, R., Saksida, L. M., Bussey, T. J., et al. (2012) · Nature Neuroscience · doi:10.1038/nn.3277 · Cited by 108
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Bartko, S. J., Romberg, C., White, B., Wess, J., Bussey, T. J., & Saksida, L. M. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.08.023 · Cited by 71
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Grant, S. G. N. (2009) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2009.74.033 · Cited by 13
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Self-citationAnimal models of neuropsychiatry revisited: A personal tribute to Teitelbaum
Robbins, T. W. (2012) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.03.005 · Cited by 10
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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
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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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