Periodic Reporting for period 3 - SYNPATH (Regulation of synaptic development and plasticity by molecular pathways linked to human evolution)
Reporting period: 2022-06-01 to 2023-11-30
The synapse is a nanoscale machine, which transfers, integrates and stores information in brain circuits. Its 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, which contributes to the formation and function of complex circuits supporting human cognitive abilities. Yet, the underlying molecular mechanisms are not known. Here we are investigating the role of molecular pathways linked to human evolution in the regulation of synaptic development and plasticity. We have previously shown that SRGAP2, one of the few genes specifically duplicated in humans, has contributed to the emergence of human features of synapses. We are using the duplications of SRGAP2 as a starting point to uncover i) fundamental mechanisms of synaptic development and plasticity, and ii) regulations specific to human synapses. This work will be important to bridge the gap in knowledge between cellular neurobiology and human brain evolution, and better understand synaptic dysfunctions in neurodevelopmental disorders.
So far, our work has unraveled the role of the glutamate receptor delta-1 in the specification of cortical circuits (Fossati et al., Neuron 2019). Its regulation by SRGAP2 might contribute to delay inhibitory synaptogenesis in human neurons or help accommodate the greater diversity of interneurons in the human brain. We have developed a 3D-CLEM (Correlative Light and Electron Microscopy) approach for the ultrastructural characterization of specific and sparse populations of synapses in the brain (Gemin et al., Plos Biol. 2021). Using this approach and morphologically-constrained modelling of synaptic integration, we have identified a population of dually-innervated spines dendritic spines in upper layer cortical pyramidal neurons and characterized its regulation by the human-specific gene SRGAP2C (Gemin et al., Plos Biol. 2021). Our work has also laid the foundation for the investigation of other human-specific genes and the molecular pathways they regulate in normal and pathological conditions, which we are currently pursuing.
The results we have obtained so far have improved our understanding of cortical network formation and challenged the dogma that ionotropic glutamate receptors solely operate in synaptic excitation. They have also provided a new imaging technique to tackle the organization and the plasticity of specific types of synaptic corrections in brain circuits. Until the end of the project, we expect to characterize molecular pathways regulated by SRGAP2C, determine the function of another human-specific gene and tackle the importance of human-specific pathways directly in neurons derived from human induced pluripotent stem cells. We will especially investigate molecular pathways at the crossroad of human evolution and neurological disorders.