Patients with this genetic variant have impaired neuronal excitability, a trait that has been linked to malfunctional synapses.
Variants of the SYNGAP1 gene may increase the risk of developing autism spectrum disorder (ASD), according to authors who published their study results in Nature Neuroscience. The study findings suggest that the disease-causing gene variation can disrupt the early development of the brain’s cortex, expanding on the previous notion that synapse malfunction was the only factor associated with autistic traits.
“Every time somebody studies SYNGAP, we find out it does something else,” said Mike Graglia, managing director of the SynGAP Research Fund, in a press release. “The dogma is that all disease-causing variants have the same impact, [but] in real life, it’s way more complicated.”
Prior to this discovery, researchers believed that ASD risk genes were mostly responsible for impairing synapse functioning. Synapses facilitate nerve cell communication, said corresponding author Giorgia Quadrato, an assistant professor of stem cell biology and regenerative medicine inthe Keck School of Medicine at the University of Southern California (USC).
The SYNGAP1 gene normally provides instructions for making a protein that regulates synapse activity in the nerve cells, and disease-causing variants of this gene can lead to autistic features.Most patients face intellectual disability, developmental delay, and epilepsy, according to authors.
Investigators conducted this study because they wanted to understand the role of the SYNGAP1 protein during brain development. The team was able to do this by studying organoids (ie, brain structures that are artificially grown from human stem cells) derived from both normal anddisease-causing variants in the SYNGAP1 gene.
“Organoids have created an opportunity to explore previously inaccessible aspects of human brain development,” said Quadrato in the press release.
The team observed that the SYNGAP1 protein could be found in radial glia cells (ie, progenitor cells that originate from the stem cells and differentiate in the developing cortex), debunking previous beliefs that this protein is only in neuron synapses.
Likewise, decreased levels of SYNGAP1 were shown to negatively affect early cortical development—this is because less SYNGAP1 in the radial glia altered their cytoskeletons, which impacted the cells’ structure and support.
Further, these altered radial glia had faster cell differentiation into dysfunctional mature nerve cells that do not form well-organized neural circuits. According to investigators, these findings suggest that the genetic variants cue the development of a disorganized cortex, and the effect of this is disordered circuitry and altered neural activity, such as impaired neuronal excitability.Further, t
his new research can assist with the development of different modalities for treating disorders caused by SYNGAP1 variants, according to Jonathan Santoro, an assistant professor of clinical neurology pediatrics at Children’s Hospital Los Angeles (CHLA).
“Ultimately, [findings] point to the importance of pursuing ASD therapies that target not only synapse function, but also early developmental defects.”
The autism-linked gene SYNGAP1 could impact early stages of human brain development, USC study reveals. Keck school of Medicine of USC. News Release. November 9, 2023. Accessed on November 20, 2023. https://www.eurekalert.org/news-releases/1007333