In a pivotal discovery, scientists have found that genes unique to human brain evolution are intricately linked to the development of neurodevelopmental disorders, such as autism and intellectual disabilities. This study highlights the profound impact of human-specific molecular mechanisms on brain function.
A team of international researchers has uncovered a significant link between two human-specific genes and crucial genes associated with neurodevelopmental disorders, offering new hope for understanding and potentially treating conditions like autism and intellectual disabilities.
In a study published in Neuron, researchers led by Pierre Vanderhaeghen, a professor of medicine at VIB-KU Leuven, in collaboration with scientists from Columbia University and Ecole Normale Supérieure, have identified a direct connection between genes linked to human brain evolution and the SYNGAP1 gene. Mutations in SYNGAP1 are known to cause intellectual disabilities and autism spectrum disorders.
The human brain is uniquely characterized by its protracted developmental timeline, particularly visible in the slow maturing of synapses — the essential connections between neurons responsible for cognition. While synapses in species like mice mature in months, human synapses take years, a process believed to be central to our advanced cognitive abilities. However, disruptions in this pathway may underpin certain neurodevelopmental disorders.
This pioneering study delves into the behavior of two genes, SRGAP2B and SRGAP2C, which are specific to humans. Initially identified in mice by Cécile Charrier in Franck Polleux’s laboratory at Columbia University, these genes were found to decelerate synapse development when introduced into mouse neurons. The current investigation aimed to determine if these genes function similarly in human neurons.
Baptiste Libé-Philippot, a postdoctoral fellow in Vanderhaeghen’s lab, led an experiment where SRGAP2B and SRGAP2C were deactivated in human neurons transplanted into mouse brains and observed over 18 months.
The results were striking.
“We discovered that when you turn off these genes in human neurons, synaptic development speeds up at remarkable levels,” Libé-Philippot said in a news release. “By 18 months, the synapses are comparable to what we would expect to see in children between five and 10 years old! This mirrors the accelerated synapse development observed in certain forms of autism spectrum disorder.”
Further analysis revealed that these genes interact with SYNGAP1 to regulate the development speed of human synapses. Astonishingly, SRGAP2B and SRGAP2C not only increase SYNGAP1 levels but can also correct some defects in neurons lacking SYNGAP1, highlighting their vital role in human-specific neurodevelopmental pathways.
“This work gives us a clearer picture of the molecular mechanisms that shape the slow development of human synapses,” Vanderhaeghen said in the news release. “It is amazing to find out that the same genes that are involved in the evolution of the human brain also have the potential to modify the expression of specific brain diseases.”
“This could have important clinical relevance: more research is needed to understand how human-specific mechanisms of brain development affect learning and other behaviors and how their dysregulation can lead to brain disorders. It becomes conceivable that some human-specific gene products could become innovative drug targets,” he added.