Synaptic scaffold evolution generated components of vertebrate cognitive complexity


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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Figure 1: Dissecting the role of Dlg paralogs in different components of cognition.
Figure 2: Distinct roles of Dlg paralogs in simple forms of conditioning and associative learning.
Figure 3: Dlg paralogs have distinct functions in cognitive flexibility and response inhibition.
Figure 4: Dlg paralogs are differentially involved in attentional processing and response control.
Figure 5: Dlg paralogs have diversified to play distinct roles in different cognitive functions.
Figure 6: Conservation of Dlg2 functions in mice and humans.


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We 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




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.

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Correspondence to Seth G N Grant.

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T.J.B. and L.M.S. consult for Campden Instruments.

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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).

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