title: Synaptic scaffold evolution generated components of vertebrate cognitive complexity.
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.
authors.affiliation: Genes to Cognition Programme, Centre for Clinical Brain Sciences and Centre for Neuroregeneration, The University of Edinburgh, Edinburgh, UK.
authors.forename: Jess
authors.initials: J
authors.lastname: Nithianantharajah
authors.forename: Noboru H
authors.initials: NH
authors.lastname: Komiyama
authors.forename: Andrew
authors.initials: A
authors.lastname: McKechanie
authors.forename: Mandy
authors.initials: M
authors.lastname: Johnstone
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Blackwood
authors.forename: David
authors.initials: D
authors.lastname: St Clair
authors.forename: Richard D
authors.initials: RD
authors.lastname: Emes
authors.forename: Louie N
authors.initials: LN
authors.lastname: van de Lagemaat
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Saksida
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Bussey
authors.forename: Seth G N
authors.initials: SG
authors.lastname: Grant
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D001245:Association Learning / Q000502:physiology; D001288:Attention / Q000502:physiology; D005075:Biological Evolution; D002755:Choice Behavior / Q000502:physiology; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D003072:Cognition Disorders / Q000235:genetics* / Q000473:pathology*; D003214:Conditioning, Classical / Q000502:physiology; D003216:Conditioning, Operant / Q000502:physiology; D017124:Conserved Sequence / Q000235:genetics; D004192:Discrimination, Psychological / Q000502:physiology; D000076122:Disks Large Homolog 4 Protein; D005108:Extinction, Psychological / Q000502:physiology; D005260:Female; D051528:Guanylate Kinases / Q000235:genetics; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009483:Neuropsychological Tests; D009687:Nuclear Proteins / Q000235:genetics; D010775:Photic Stimulation; D011930:Reaction Time / Q000235:genetics; D000074407:SAP90-PSD95 Associated Proteins; D013569:Synapses / Q000235:genetics*; D014110:Touch / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: C116869:DLG3 protein, human; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000074407:SAP90-PSD95 Associated Proteins; D014157:Transcription Factors; C501445:Dlg2 protein, mouse; D051528:Guanylate Kinases