New York, Oct 7: A team of scientists have discovered the impact of a multitude of genes that are associated with neurodevelopmental disorders, including autism, but whose effects on human brain development were previously unknown.
Studies have implicated at least 500 genes in such disorders. But scientists have no idea exactly how defects in most of these genes impair brain function.
The new findings, led by a team from the Stanford University in the US, are likely to accelerate drug development for neurodevelopmental disorders.
There are two main classes of neurons in the cerebral cortex: excitatory and inhibitory. Excitatory neurons fire impulses that activate other neurons, while inhibitory neurons’ firing blocks other neurons from firing. Inhibitory and excitatory neurons integrate to form circuits, shaping signalling activity in the brain.
In humans, as many as half of all cells in the cerebral cortex, the brain’s outermost and most recently evolved layer, are inhibitory. Scientists theorised that an imbalance in the number or function of inhibitory neurons compared with excitatory neurons might be at least partly responsible for autism spectrum disorder and epilepsy.
“If that’s true, you could find ways to alter the functional balance of these cells in the cortex as a therapeutic approach for these disorders,” said Sergiu Pasca, Professor of Psychiatry and Behavioral Sciences at the varsity.
But first, he wondered, how do you make sense of the enormous collection of genes that have been implicated in these conditions but whose impacts are largely unknown?
Does the existence of hundreds of genes associated with disease mean that there are hundreds of different types of neurodevelopmental disorders, each requiring a different remedy? Or might several different genes converge and lead to similar pathology, or some particular aspect of it?
“If it’s the latter, a cluster of gene defects that all produce a similar physiological deficit might be amenable to a single type of treatment,” Pasca said.
To explore, the team used two cutting edge technologies. They paired cortical organoids, developed using human induced pluripotent stem (iPS) cells and a gene editing tool CRISPR and tested 425 genes that have been linked to neurodevelopmental disorders. Their test aimed to determine which ones interfere with the generation and migration of interneurons.
From those iPS cells, the researchers generated subpallial organoids. Some showed no fluorescence at all after 44 days in a dish, indicating their failure to generate interneurons.
By sequencing the genomes of these organoids, the researchers could tell which gene had been disabled by the CRISPR scissors, resulting in defective interneuron generation. They identified 13 such genes.
They also identified another 33 genes that, when missing, prevented interneurons from travelling to the cerebral cortex. All told, 46 genes, of the 425, appeared to affect the nerve cells that inhibit their neighbours, leading to an imbalance.
“The identification of 46 genes -- close to 10 per cent of all known neurodevelopmental-disorder-associated genes -- whose dysfunction impairs interneuron development points to a subgroup of neurodevelopmental disorders that are characterised by inadequate inhibition of excitatory cortical neurons,” Pasca said.
Some of these genes have been previously uncharacterised, and their function unsuspected, Pasca said.