Molecular and Cellular Mechanisms Underlying Human-Specific Evolution of Cortical Connectivity

Two prominent hallmarks of the human brain are the prolonged maturation time of neuronal circuits and a significant increase in cortical neuron connectivity. These features have been hypothesized to underlie the emergence of higher cognitive functions in modern humans. However, little is known about the molecular changes that have led to the emergence of human-specific traits of cortical development and function. Our attention has recently focused on gene duplications that are unique to the human genome. One such gene is SRGAP2: the ancestral copy, SRGAP2A, promotes excitatory (E) and inhibitory (I) synapse maturation and limits the density of both E and I synapses made onto cortical pyramidal neurons (Charrier et al. Cell 2012; Fossati et al. Neuron 2016). Partial duplication of SRGAP2A resulted in a human-specific paralog, SRGAP2C, which binds to and inhibits SRGAP2A function. Deletion of SRGAP2A or expression of SRGAP2C in mouse cortical pyramidal neurons leads to the emergence of phenotypic traits characterizing human cortical neurons, including increased E and I synaptic density and a protracted period of synaptic maturation. However, how this increased density of synapses and prolonged maturation affects the structure and function of cortical circuits remains unknown and constitutes the main goal of our current project. I will present some new results probing changes in circuit structure and function upon SRGAP2A loss-of-function or ‘humanization’ of SRGAP2C expression in mouse cortical circuits.  Our results provide new insights into the significance of the emergence of human-specific SRGAP2C gene on brain evolution by defining its impact on synaptic organization and circuit function.