Human synaptic neoteny requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition

Baptiste Libé‐Philippot; Ryohei Iwata; Aleksandra J. Recupero; Keimpe D. B. Wierda; Martyna Ditkowska; Vaiva Gaspariunaite; Ben Vermaercke; Eugénie Pezé-Heidsieck; Daan Remans; Cécile Charrier; Franck Polleux; Pierre Vanderhaeghen

doi:10.1101/2023.03.01.530630

NeurosciencebioRxivMar 1, 2023

Preprint

Human synaptic neoteny requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition

Baptiste Libé‐Philippot iD, Ryohei Iwata iD, Aleksandra J. Recupero iD, Keimpe D. B. Wierda iD, Martyna Ditkowska iD, Vaiva Gaspariunaite iD, Ben Vermaercke iD, Eugénie Pezé-Heidsieck iD, Daan Remans iD, Cécile Charrier iD, Franck Polleux iD, Pierre Vanderhaeghen iD

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Abstract

Human-specific (HS) genes are potential drivers of brain evolution, but their impact on human neuron development and disease remains unclear. Here we studied HS genes SRGAP2B/C in human cortical projection neurons (CPNs) in vivo, using xenotransplantation in the mouse cortex. Downregulation of SRGAP2B/C in human CPNs greatly accelerated synaptic development, indicating their requirement for human-specific synaptic neoteny. SRGAP2B/C acted by downregulating their ancestral paralog SRGAP2A, thereby upregulating postsynaptic levels of SYNGAP1, a major intellectual deficiency/autism spectrum disorder (ID/ASD) gene. Combinatorial genetic invalidation revealed that the tempo of synaptogenesis is set by a balance between SRGAP2A and SYNGAP1, which in human CPNs is tipped towards neoteny by SRGAP2B/C. Our results demonstrate that HS genes can modify the phenotypic expression of ID/ASD mutations through regulation of synaptic neoteny. One-Sentence SummaryHuman-specific genes SRGAP2B/C control human cortical neuron neoteny by regulating the function of neurodevelopmental disorder gene SYNGAP1