Human-specific modifiers of synapses in development, plasticity and disorders

The function of the brain relies on an intricate network of neurons connected by synapses that enable us to feel, think, learn, act, communicate and adapt our behavior to the ever-changing world. Although the molecular composition and organization of synapses are overall conserved across mammals, a large body of evidence indicates that synapses are differentially regulated in humans. This specialization of human synapses is at the heart of what makes us human. It contributes to the increase in connectivity that characterizes the human neocortex. It also extends the period of synaptic maturation during which cognitive and social experiences sculpt developing cortical circuits and many neurodevelopmental disorders manifest. In this project, we will test the hypothesis that human-specific genetic innovations enhance the role of the environment in the development of synapses in cortical circuits and impact the pathophysiology of neurodisorders. Building on recent advances in our understanding of the human genome, we will determine how human-specific genetic innovations modify the cell biology of synapses, from synaptic connectivity and maturation to synaptic plasticity and pathological dysfunctions. We will combine cutting-edge mouse and human models compatible with investigation of synapse cell biology in integrated circuits together with a multidisciplinary approach based on in vivo molecular manipulations, electrophysiology, microscopy and omics technologies. This will allow us to gain a comprehensive understanding of fundamental mechanisms and illuminate species differences between mouse and human at the synapse and in neurodisorders, in a way not previously possible and with broad implications for the development of therapeutic strategies.