How the rich and diverse set of vertebrate higher cognitive functions and the susceptibility to human mental illness evolved is unknown. The vertebrate cognitive repertoire comprises multiple forms of learning, attention and executive functions, which are selectively disrupted in mental disorders, such as schizophrenia, autism and intellectual disability. Two whole genome duplications at the base of the vertebrate lineage generated gene paralogs that expanded and diversified the molecular complexity of simpler invertebrate synapse proteomes. Here we use computerized touchscreen tests for higher cognitive functions in mice and humans to examine the phenotype of mutations in one such set of paralogs, the Dlg family of synaptic scaffold proteins. Comparing mice carrying mutations in four Dlg paralogs shows simple associative learning required Dlg4 function while Dlg2 and Dlg3 diversified to play specific and opposing roles in complex learning and attentional processes. We compared the selective impairments of the mouse Dlg2 mutation with humans carrying Dlg2 mutations using homologous cognitive test apparatus and found a high degree of similarity in the selective disruption of the cognitive repertoire by Dlg2 mutations in both species. In humans, Dlg2 mutations are associated with schizophrenia and mutations in Dlg3 causes intellectual disability. Our data demonstrate that paralogous gene duplication and diversification initiated over 500 million years (My) ago diversified the regulation of vertebrate higher cognitive functions and that the constraint in structure and function of these genes within the last 100 My conserved the specific cognitive roles of genes underlying human mental illness. The demonstrated conservation in cognitive function using homologous psychological test apparatus also provides a new approach to translating the genetic studies of mental illness into therapeutic benefit.
|Publication status||Published - 18 Jul 2012|
|Event||8th Fens Forum of Neuroscience - Centre Convencions Internacional Barcelona (CCIB) Plaça de Willy Brandt 11-14 08019 Barcelona , Barcelona, Spain|
Duration: 14 Jul 2012 → 18 Jul 2012
|Conference||8th Fens Forum of Neuroscience|
|Period||14/07/12 → 18/07/12|