Researchers from the Stanford School of Medicine, USA, have narrowed the number of genes causing neurodevelopmental disorders to 46 –from a previous list of 661 genes. They sorted the genes based on how they hamper brain development.
The study published in Nature dated 27 September found that this shorter list of genes could help understand neurodevelopmental disorders better. This in turn quickens the process of drug discovery for the conditions.
“Neurodevelopmental disorders have a strong genetic basis, and some are caused by mutation in a single gene,” Dr Xiangling Meng, co-author of the study and a postdoctoral researcher from the Department Of Psychiatry And Behavioural Sciences at Stanford School of Medicine, USA, tells Happiest Health.
Previous studies identified around 661 genes that could potentially cause neurodevelopmental disorders like autism and epileptic conditions.
The current research has narrowed this list to 46 genes, which is easier to target than a large gene pool, says Dr Meng. “[Also, understanding] what goes awry when [the genes] mutate can explain the pathogenesis of neurodevelopmental disorders,” she explains.
Two types of neurons
The researchers believe that the genes could be responsible for shaping the signalling circuits in the brain; they are found in the outermost region called the cerebral cortex.
This region has two types of neurons. Excitatory neurons fire impulses to activate other neurons, and inhibitory neurons block neurons from overfiring. These two neurons work in tandem to form circuits that shape the brain’s signalling process.
A delicate balance
Almost half of the neurons in the cortex region consist of inhibitory neurons. An imbalance in the excitatory and inhibitory neurons might be responsible for neurodevelopmental disorders.
Restoring the balance could act as a therapeutic target for such conditions. This is where the researchers of the current study believe that targeting the genes that cause this imbalance could hold the solution.
Two technologies used
But then arises the conundrum of whether all the 661 genes are involved in these neurodevelopmental disorders. The researchers found answers by using induced pluripotent stem cells.
They engineered these versatile cells to form two small clusters of cells – one to resemble the human cortex and one to resemble another region called the subpallium.
The subpallium region of the brain helps to produce inhibitory neurons. During brain development, these neurons move towards the excitatory neurons in the cerebral cortex to form the signalling circuits.
Preventing cell clusters
The researchers say subpallium and cortical cell clusters fuse when kept next to each other. To identify which genes could prevent the clusters from fusing, they used CRISPR technology.
They found that 13 genes caused the defective formation of inhibitory neurons, while 33 other genes derailed the migration of the inhibitory neurons into the cortex.
“All these 46 genes have been associated with neurodevelopmental conditions, specifically to autism,” says Dr Meng.
According to her, their work unveils the function of many genes linked with neurodevelopmental disorder and indicates that an impaired development of inhibitory neurons causes disease progression.
“It indicates that we can target these neurons to treat conditions associated with mutations of the genes,” she says.
Link to study: Assembloid CRISPR screens reveal impact of disease genes in human neurodevelopment
