Link discovered between two human-specific genes and the SYNGAP1 gene, which is associated with intellectual disability and autism spectrum disorders
14th October 2024: A team of researchers led by Prof. Pierre Vanderhaeghen (VIB-KU Leuven), in collaboration with scientists from Columbia University and Ecole Normale Supérieure, has discovered a link between two human-specific genes, SRGAP2B and SRGAP2C, and the SYNGAP1 gene, which is associated with intellectual disability and autism spectrum disorders. Their study, published in Neuron (open access), provides a direct connection between human brain evolution and neurodevelopmental disorders.
The human brain is unique among mammals due to its prolonged development, particularly in the maturation of synapses in the cerebral cortex, which takes years compared to months in other species like macaques or mice. This extended development, known as neoteny, is believed to be crucial for advanced cognitive and learning abilities in humans. However, disruptions in this process may lead to neurodevelopmental disorders.
Previously, Vanderhaeghen’s lab identified that the prolonged development of the human cerebral cortex is driven by human-specific molecular mechanisms. In their latest study, they explored the role of SRGAP2B and SRGAP2C genes, which were initially identified by Cécile Charrier in Prof. Franck Polleux’s lab at Columbia University. These genes slow down synapse development when introduced into mouse neurons. To understand their function in human neurons, Dr. Baptiste Libé-Philippot, a postdoctoral fellow in Vanderhaeghen’s lab, switched off these genes in human neurons and transplanted them into mouse brains, monitoring synapse development over 18 months.
The results showed that turning off SRGAP2B and SRGAP2C in human neurons accelerated synaptic development to levels comparable to those seen in children aged five to ten years. This mirrors the accelerated synapse development observed in some forms of autism spectrum disorder.
Further investigation revealed that SRGAP2B and SRGAP2C interact with the SYNGAP1 gene to regulate the speed of synapse development. Remarkably, these genes can increase SYNGAP1 levels and even reverse some defects in neurons lacking SYNGAP1. This discovery enhances our understanding of how human-specific molecules influence neurodevelopmental disease pathways, shedding light on the prevalence of such disorders in humans.
Prof. Vanderhaeghen expressed optimism about the future, noting that this research provides a clearer picture of the molecular mechanisms shaping the slow development of human synapses and highlights the potential of these genes to modify neurodevelopmental disease pathways.
Reference:
Libé-Philippot, B., et al. (2024) Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition. Neuron. doi.org/10.1016/j.neuron.2024.08.021.
