CORTEX conference by Franck Polleux

The human neocortex underlies most of our higher cognitive functions. The emergence of complex forms of written and oral communication, our propensity to develop new technologies and our ability to produce artistic representations of our imagination, our experiences and our emotions are some of the remarkable cognitive features characterizing modern humans. Phenotypic traits that are unique to the human lineage are considered to be the result of selective pressures on our genome since our divergence from the Pan lineage approximately >7 million years ago. The decoding of the human and chimpanzee genomes provided a template to help understand how genomic changes resulted in the evolution of human cognition. More than a decade later, the functional consequences of such genomic changes are still elusive with a few exceptions. One of the largest class of genomic changes, gene duplications, represents a major driving force in evolution. Recent advances in evolutionary genomics have identified a burst of human-specific gene duplications that occurred after separation from our common ancestor with non-human primates. These studies have identified approximately 25 genes duplicated specifically in the human lineage i.e. not in any non-human primates for which we have complete genomic data (Chimpanzee, Gorilla, Orangutan). Several groups have hypothesized that these human-specific gene duplications participated in the emergence of human-specific traits of brain development and function. However, until recently, it has been exceedingly difficult to assess the cellular, molecular and developmental impact of human-specific gene duplications on the organization and function of cortical circuits, and ultimately their cognitive and behavioral consequences. The roadblocks for probing the evolutionary significance of human-specific gene duplications are numerous: the absence of functional data on the ancestral genes and their human-specific paralogs, a lack of data regarding their expression patterns in the developing and adult human brain, and a dearth of experimental paradigms to test the functions of humanspecific gene duplications during brain development. Recently, in studies aimed at defining the evolutionary significance of human-specific duplications, my lab characterized the function of a gene called SRGAP2A which among other functions, plays a critical role in promoting excitatory synaptic maturation and limits synaptic density during cortical development. These recent results suggested for the first time that inhibition of SRGAP2 function by its human-specific paralog SRGAP2C contributed to the evolution of the human cortical circuits by slowing the rate of excitatory synapse maturation and allowing the emergence of more excitatory synapses per pyramidal neuron, which are critical features of human pyramidal neurons. This study provided the first experimental paradigm to study rigorously the biological significance of human-specific gene duplication during brain development. More recently, we also identified that SRGAP2A plays a critical role in regulating inhibitory synaptic development in pyramidal neurons (see below Fig. 2) and that expression of SRGAP2C inhibits this function of SRGAP2A leading to significant changes in the maturation, density and distribution of inhibitory synapses in cortical microcircuits (Charrier and Polleux, submitted). Based on our recent results, we propose to test the developmental and functional consequences of the structural changes induced by human-specific gene duplication of SRGAP2A cortical microcircuits and to determine the behavioral outcomes of these changes on the performance of cortical circuits. The long-term scientific goal of this research program is to apply the concepts and techniques developed in my lab over the past 10 years to determine the evolutionary significance of human-specific gene duplications as modifiers of cortical development. Our aim is to test if this type of genomic modifications represents an evolutionary relevant substrate for the emergence of new functional properties in cortical circuits. This project will tackle with unprecedented relevance the relationship between genes, neural circuits and behavior in an evolutionary framework.