Periodic Reporting for period 4 - SYNPATH (Regulation of synaptic development and plasticity by molecular pathways linked to human evolution)
Reporting period: 2023-12-01 to 2024-12-31
The synapse is a nanoscale machine, which transfers, integrates and stores information in brain circuits. Its proper function relies on multimolecular networks of interactions whose composition and dynamics shape synaptic transmission. A large body of evidence indicates that synapses specialized in humans. Human synapses are more densely distributed along dendrites and their period of maturation is protracted compared to rodent or non-human primate synapses. The rules governing their plasticity also differ from the other mammalian species studied so far. These traits contribute to the formation and function of complex circuits supporting human cognitive abilities, and their alterations cause neurodevelopmental disorders. Yet, the underlying molecular mechanisms are largely unknown. The goal of this project was to decipher the role of molecular pathways linked to human evolution in synaptic development and plasticity.
We focused on Slit-Robo Rho-GTPase-activating protein 2 (SRGAP2), one of the few genes specifically duplicated in humans, and the only one implicated at synapses so far. Using the duplications of SRGAP2 as a thread, and a multiscale approach ranging from the molecule to the circuit, our work uncovered fundamental mechanisms underlying the specification of cortical circuits and novel forms of synaptic plasticity. We developed a methodology for the ultrastructural investigation of specific populations of synapses in intact circuits with single cell resolution. We demonstrated that the human-specific gene SRGAP2C extends the period of synaptic maturation at the core of synapses, by slowing the assembly of postsynaptic scaffolds and enhancing the accumulation of proteins that limit synaptic activity. Our work highlighted interactions between human specific genes and genes mutated in neurodevelopmental disorders, which important consequences for our understanding of the evolution of the human brain and its dysfunctions in neurodisorders. Together, our results were published in three major articles and two collaborative articles. We also published three review articles.
Despite recent advances on the expansion of the human cortex, little is known on the mechanisms underlying the specialization of human synapses and cortical circuits at the cellular and molecular levels. Our work has uncovered molecular pathways that diverge in human neurons and underly characteristic features of human synapses in cortical circuits, including their increased connectivity compared to other mammalian species and their neoteny. By investigating the interaction network of SRGAP2, we discovered molecular intersections between human brain evolution and neurodevelopmental disorders. These discoveries are changing our vision of these disorders and are now suggesting new avenues for therapeutic strategies.
In addition, our results challenged a long-standing dogma in neurotransmitter receptor biology, they highlighted a molecular code for cortical circuit wiring and a novel form of synaptic plasticity. They also provided a new correlative micorscopy technique to tackle the organization and the plasticity of specific types of synaptic corrections in brain circuits. These results represent fundamental and methodological advances in neurosciences.
In addition, our results challenged a long-standing dogma in neurotransmitter receptor biology, they highlighted a molecular code for cortical circuit wiring and a novel form of synaptic plasticity. They also provided a new correlative micorscopy technique to tackle the organization and the plasticity of specific types of synaptic corrections in brain circuits. These results represent fundamental and methodological advances in neurosciences.