Premature development of human neurons is linked to autism

The mechanisms behind intellectual impairment and autism are mostly unknown. Mutations in a gene called SYNGAP1 disrupt the long-term growth of human neurons, which is thought to be essential for normal cognitive function. Their research, published in NeuronThis has important implications for our understanding and treatment of intellectual disability and autism.

What is neoteny and does it have a connection to autism?

The human brain is known for its extremely long growth among mammals. Unlike other animals, the neurons in our brain, especially in the cerebral cortex, which is the primary site of cognitive activities, take years to fully develop. This process, known as neoteny, is thought to be crucial for the evolution of our species' superior cognitive functions. Intellectual disability and some forms of autism may be attributed to disruptions in this extended developmental process. To date, this idea has not been tested in human neurons.

A look at the growing brain

Introduction to the gene SYNGAP1. Previous research has shown that mutations in this gene are the primary cause of several diseases. However, the specific consequences of its disruption on human cortical neurons are still poorly understood. Until recently, a major obstacle to understanding human brain developmental diseases was the lack of effective experimental methods to observe human cortical neuron growth in the living brain.

Scientists from the VIB-KU Leuven Centre for Brain and Disease Research and NERF (Neuro-Electronics Research Flanders, supported by imec, KU Leuven and VIB) have discovered that SYNGAP1 is essential for the extended growth of human cortical neurons. This establishes a link between accelerated neural development and intellectual impairment or autism.

To study how the SYNGAP1 mutation affects living human neuron development, the researchers used a xenotransplantation model, in which they transplanted human neurons with the SYNGAP1 mutation into the brains of mice and then examined their development and function.

How SYNGAP1 mutant neurons alter brain circuit integration

The researchers examined the consequences of the mutation at the circuit level in human neurons transplanted into the mouse brain – connections between neurons that play specific roles in the brain. “We observed that the SYNGAP1 mutant neurons looked normal in most aspects, but they displayed a strong acceleration in their development. Most surprisingly, they connected with other neurons much faster,” explains Dr. Ben Vermaerke, first author of the paper.

Dr. Vermaak and his colleagues found that as neurons become deficient, they integrate rapidly into cortical circuits and respond to visual stimuli months ahead of the normal developmental schedule, meaning that the rapid maturation of neurons results in precocious functionality in brain circuits.

Professor Pierre Vanderhaegen says, “This accelerated development of SYNGAP1 mutant neurons may alter the early function and plasticity of infant brain circuits, although this needs to be studied further by experimental and clinical investigations. The crucial role of neoteny for normal human brain development highlights how its disruption can lead to neurodevelopmental diseases. Early defects in the development of human cortical neurons may have important implications for the diagnosis and treatment of patients affected by SYNGAP1, and potentially also in patients presenting with intellectual disability or other forms of autism.”

Professor Vincent Bonin concludes, “The transplantation model we have developed enables us to study living human neuronal diseases for the first time, at both the functional and circuit levels. This success creates a promising model for understanding neurological diseases and testing new therapies.”

Reference:

1. When faster isn't better: New study links premature growth of human neurons to brain development disorders (https://www.eurekalert.org/news-releases/1053579)

Source-MedIndia