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

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thank K. Elsegood and D. Fricker for mouse husbandry and genotyping, T.W. Robbins for advice on CANTAB, J. Barnett for assistance with CANTAB control data and T.W. Robbins and T.J.

O'Dell for comments on the manuscript. Figure illustration contribution by D.J. Maizels. J.N., N.H.K., L.N.L. and S.G.N.G. was supported by The Wellcome Trust, Genes to Cognition

Program, The Medical Research Council (MRC) and European Union programs (Project GENCODYS no. 241995, Project EUROSPIN no. 242498 and Project SYNSYS no. 242167). M.J. was supported by grants

from RS Macdonald Charitable Trust and Academy of Medical Sciences/The Wellcome Trust. AUTHOR INFORMATION Author notes * Timothy J Bussey and Seth G N Grant: These authors contributed

equally to this work. AUTHORS AND AFFILIATIONS * Genes to Cognition Programme, Centre for Clinical Brain Sciences and Centre for Neuroregeneration, The University of Edinburgh, Edinburgh, UK

Jess Nithianantharajah, Noboru H Komiyama, Louie N van de Lagemaat & Seth G N Grant * Genes to Cognition Programme, The Wellcome Trust Sanger Institute, Hinxton, UK Jess

Nithianantharajah, Noboru H Komiyama, Louie N van de Lagemaat & Seth G N Grant * Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK Andrew

McKechanie, Mandy Johnstone & Douglas H Blackwood * The Patrick Wild Centre, The University of Edinburgh, Edinburgh, UK Andrew McKechanie * Institute of Medical Sciences, University of

Aberdeen, Aberdeen, UK David St Clair * School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, UK Richard D Emes & Timothy J Bussey * Department of

Experimental Psychology, University of Cambridge, Cambridge, UK Lisa M Saksida & Timothy J Bussey * The Medical Research Council and The Wellcome Trust Behavioral and Clinical

Neuroscience Institute, University of Cambridge, Cambridge, UK Lisa M Saksida & Timothy J Bussey Authors * Jess Nithianantharajah View author publications You can also search for this

author inPubMed Google Scholar * Noboru H Komiyama View author publications You can also search for this author inPubMed Google Scholar * Andrew McKechanie View author publications You can

also search for this author inPubMed Google Scholar * Mandy Johnstone View author publications You can also search for this author inPubMed Google Scholar * Douglas H Blackwood View author

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Emes View author publications You can also search for this author inPubMed Google Scholar * Louie N van de Lagemaat View author publications You can also search for this author inPubMed 

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author inPubMed Google Scholar * Seth G N Grant View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS J.N., N.H.K., L.M.S., T.J.B. and S.G.N.G.

conceived and designed the experiments. J.N. performed all mouse experiments and all analysis in the manuscript. A.M. administered CANTAB tests. M.J. performed _DLG2_ CNV genotyping. A.M.,

D.H.B. and D.S.C. collected clinical data. R.D.E. provided sequence analysis and L.N.L. gene expression correlation analysis. J.N., T.J.B. and S.G.N.G. wrote the manuscript with input from

all authors. CORRESPONDING AUTHOR Correspondence to Seth G N Grant. ETHICS DECLARATIONS COMPETING INTERESTS T.J.B. and L.M.S. consult for Campden Instruments. SUPPLEMENTARY INFORMATION

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Nithianantharajah, J., Komiyama, N., McKechanie, A. _et al._ Synaptic scaffold evolution generated components of vertebrate cognitive complexity. _Nat Neurosci_ 16, 16–24 (2013).

https://doi.org/10.1038/nn.3276 Download citation * Received: 11 June 2012 * Accepted: 10 November 2012 * Published: 02 December 2012 * Issue Date: January 2013 * DOI:

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