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Fundamental mechanisms and human-specific regulations of synaptic development and plasticity

Head of Project : Cécile Charrier

Synapses are multimolecular nanomachines that ensure the proper connectivity of neuronal circuits, integrate diverse inputs into biochemical reactions and allow adaptive responses to the environment. Small changes in the molecular organization of synapses can lead to profound modifications of behavioral and cognitive abilities, as frequently observed in neurodevelopmental and psychiatric disorders. Small changes also appeared during human evolution. Although poorly characterized, they underlie the distinctive developmental and physiological properties of human synapses and are at the core of what makes us humans.

We are investigating the role of molecular pathways linked to human evolution in the development and plasticity of synaptic connections in the neocortex. Our goal is to elucidate fundamental principles that are common to all mammals, and uncover regulations that are specific to humans. We employ a multidisciplinary approach in mouse and human models based on sparse in vivo manipulations in intact cortical circuits, proteomics, electrophysiology, as well as confocal, super-resolutive, and correlative microscopy.

Our recent work has focused on SRGAP2, one of the few genes specifically duplicated in the human lineage. We have demonstrated that the human-specific copy of SRGAP2 inhibits the ancestral protein, which leads to the emergence of human features of synapses such as their protracted developmental period and their increased density along dendrites. By investigating the underlying molecular basis, we have unraveled an intrinsic mechanism coordinating the development of excitatory and inhibitory synapses.

Participants : C. Charrier, M. Fossati, N. Assendorp, O. Gemin, S. Colasse and P. Rostaing.

Funding : ANR, Fyssen Foundation

Maffei A, Charrier C, Caiati MD, Barberis A, Mahadevan V, Woodin MA, Tyagarajan SK (2017) Emerging Mechanisms Underlying Dynamics of GABAergic Synapses. J Neurosci. 37:10792-10799

Fossati M, Pizzarelli R, Schmidt ER, Kupferman JV, Stroebel D, Polleux F, Charrier C (2016) SRGAP2 and Its Human-Specific Paralog Co-Regulate the Development of Excitatory and Inhibitory Synapses. Neuron 91:356-69

Charrier C, Polleux F (2012) [How human-specific SRGAP2 gene duplications control human brain development]. Med Sci (Paris) 28:911-4

Charrier C, Joshi K, Coutinho-Budd J, Kim JE, Lambert N, de Marchena J, Jin WL, Vanderhaeghen P, Ghosh A, Sassa T, Polleux F (2012) Inhibition of SRGAP2 function by its human-specific paralogs induces neoteny during spine maturation. Cell 149:923-35