The mechanisms behind intellectual impairments and autism are mostly unknown. Mutations in a gene called SYNGAP1 disrupt the prolonged development of human neurons, which is thought essential for normal cognitive function. Their research, published in Neuron, has important implications for our understanding and treatment of intellectual impairments and autism.

What is Neoteny and is it Linked to Autism?

The human brain stands out among mammals for its extremely protracted growth. Unlike in other animals, neurons in our brain, particularly in the cerebral cortex, which is the primary site of cognitive activities, take years to fully grow. This process, known as neoteny, is thought to be important for the development of our species’ superior cognitive functions. Some forms of intellectual disability and autism may be attributed to disruptions in this extended developmental process. Until today, this idea has not been tested in human neurons.

A Look Into the Growing Brain

Introducing the gene SYNGAP1. Previous research has shown that mutations in this gene are a primary cause of many diseases. However, the specific repercussions of its disruption on human cortical neurons remained little understood. Until recently, a major impediment to understanding human brain developmental illnesses was a lack of effective experimental methods for observing human cortical neuron growth in the living brain.

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

To study how the SYNGAP1 mutation impacts human neuron development in vivo, the researchers utilized a xenotransplantation model in which they grafted human neurons with the SYNGAP1 mutation into mice’s brains and then investigated their development and function.

How SYNGAP1 Mutant Neurons Transform Brain Circuit Integration

The researchers investigated the consequences of a mutation in transplanted human neurons in the mouse brain at the circuit level-connections between neurons that fulfill specific roles in the brain.

“We saw that the SYNGAP1 mutant neurons looked normal in most aspects, but that they displayed a strong acceleration of their development. Most strikingly, they connected much faster with other neurons,” explains Dr. Ben Vermaercke, first author of the paper.

Dr. Vermaercke and his colleagues discovered that deficient neurons integrated faster into cortical circuits and responded to visual stimuli months before the normal developmental schedule, implying that the neurons’ faster maturation resulted in precocious functionality within brain circuits.

Prof. Pierre Vanderhaeghen adds, “This accelerated development of SYNGAP1 mutant neurons could alter the early function and plasticity of infant brain circuits, although this needs to be studied further by experimental and clinical investigations. The important 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 could have important implications for the diagnosis and treatments of the patients affected by SYNGAP1, and potentially in patients presenting other forms of intellectual disability or autism.”

Professor Vincent Bonin concludes, “The transplantation model we developed enables, for the first time, the study of human neuronal diseases in vivo at both the functional and circuit levels. This breakthrough constitutes a promising model for understanding neurological diseases and testing new treatments.”

References:

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

Source-Medindia