Autism Spectrum Disorders (ASDs) are neurodevelopmental conditions characterized by difficulties with social interaction, communication, and repetitive patterns of behavior. The SHANK3 gene, associated with mutations in specific cases of ASD, plays a crucial role in both neurons and cells responsible for myelination, called oligodendrocytes (OLs). Researchers have managed to reverse this mutation and improve communication between brain regions.
Autism Spectrum Disorders (ASDs) encompass a group of neurodevelopmental conditions. These conditions are marked by difficulties with social interaction, communication, repetitive behaviors, and restricted interests, among other characteristics that can vary in severity between individuals.
Although scientists are continually investigating their causes, complete understanding is still limited. However, it is already known that ASDs have a strong genetic influence, with certain genes, such as SHANK3, being particularly associated with specific cases of ASD.
The SHANK3 gene is vital to the synaptic function of neurons, particularly at excitatory synapses, where communication between neurons occurs. It helps connect glutamate receptors to the internal structures of neurons, directly influencing the transmission of signals in the brain.
When there are mutations in SHANK3, problems such as changes in the structure of neurons, reduced activity of glutamate receptors, and changes in the normal patterns of connection between brain cells arise.
These factors contribute to the cognitive and behavioral challenges seen in individuals with ASD.
Myelin is a protective layer that surrounds axons, allowing electrical signals in the brain to be transmitted quickly and efficiently.
It is produced by specialized cells called oligodendrocytes (OLs), which undergo a complex development process before becoming functional.
Oligodendrocytes are highly influenced by the chemical and electrical signals sent by neurons, especially glutamate. Recent studies indicate that SHANK3 also plays a role in oligodendrocytes, but the details of this role are still not entirely clear.
Oligodendrocyte. Source: Nature portfolio
Mutations in SHANK3 can affect how oligodendrocytes receive and interpret glutamate signals, impairing their maturation and myelin production. This results in problems with the electrical conductivity of axons and general communication between brain regions, which can worsen symptoms associated with ASD.
To better understand how mutations in SHANK3 affect brain development, researchers use animal models and human stem cells. For example, a mouse model called InsG3680 has been developed with a specific mutation in the SHANK3 gene that is similar to that found in some human cases of ASD.
These mice have significant problems with myelination, reduced expression of proteins essential to myelin, and changes in brain structure that affect motor skills and brain function.
Furthermore, induced pluripotent stem cells (iPSCs) derived from patients with the SHANK3 mutation were used to study the effects of the mutation in human cells. These cells showed defects similar to those observed in mice, confirming the clinical relevance of these findings.
Reduced expression of transcripts encoding postsynaptic proteins in OPCs derived from InsG3680 mice and abnormal differentiation of InsG3680-OL.
Recent research by researchers at Tel Aviv University has revealed that SHANK3 plays an important role in oligodendrocytes, similar to its role in neurons.
In the InsG3680 mouse model, the mutation was observed to lead to a reduction in key proteins related to myelination, such as PLP1, MBP, and MOG. In addition, they also identified defects in myelin structure and signal conduction through axons, and motor performance problems associated with white matter dysfunction in the brain.
In parallel, studies with iPSCs from patients with the mutation confirmed deficits in human oligodendrocytes derived from these cells.
One of the most promising findings is that restoring SHANK3 levels in cell cultures can reverse some of the observed defects. This opens the way for future therapeutic approaches, which could focus on repairing or replacing SHANK3 functions in different types of brain cells.
Increased expression of Psd95 and NR1 after restoration of SHANK3 in primary cultures of InsG3680 OPCs. This means that after correcting the mutation in the SHANK3 gene, there was an increase in the production of two essential proteins called Psd95 (linked to signal transmission between brain cells) and NR1 (part of a receptor important for communication between neurons). (A) Representative images of SHANK3 expression in primary culture of transfected InsG3680 OPCs. (B) Representative images of SHANK3 and Psd95 expression (left). (C) A significant correlation was found between SHANK3 and Psd95 expression levels. (D) A significant increase in Psd95 expression levels in transfected cells compared to untransfected cells. (E) Representative image of SHANK3 and NR1 expression. (F) A significant correlation was found between the expression levels of SHANK3 and NR1. (G) A significant increase in the expression levels of NR1 in transfected cells compared to non-transfected cells.
These findings reinforce the importance of the SHANK3 gene not only for neurons but also for oligodendrocytes and the myelination process, which is crucial for brain communication.
This advance in the understanding of the genetic and cellular mechanisms underlying ASD may lead to new treatment strategies, improving the quality of life of people affected by these disorders.
READ MORE:
Shank3 mutation impairs glutamate signaling and myelination in ASD mouse model and human iPSC-derived OPCs
NBAR FISCHER, SOPHIE SHOHAT, YAEL LEICHTMANN-BARDOOGO,
RITU NAYAK, GAL WIENER, IDAN ROSH, AVIRAM SHEMEN, UTKARSH TRIPATHI, MAY ROKACH, ELA BAR, YARA HUSSEIN, ANA CAROLINA CASTRO,
GAL CHEN, ADI SOFFER, SARI SCHOKOROY-TRANGLE,
GALIT ELAD-SFADIA, YANIV ASSAF, AVI SCHROEDER,
PATRICIA MONTEIRO, SHANI STERN, BEN M. MAOZ , AND BOAZ BARAK
SCIENCE ADVANCES. 11 Oct 2024. Vol 10, Issue 41
DOI: 10.1126/sciadv.adl4573
Abstract:
Autism spectrum disorder (ASD) is characterized by social and neurocognitive impairments, with mutations of the SHANK3 gene being prominent in patients with monogenic ASD. Using the InsG3680 mouse model with a Shank3 mutation seen in humans, we revealed an unknown role for Shank3 in postsynaptic oligodendrocyte (OL) features, similar to its role in neurons. This was shown by impaired molecular and physiological glutamatergic traits of InsG3680-derived primary OL cultures. In vivo, InsG3680 mice exhibit significant reductions in the expression of key myelination–related transcripts and proteins, along with deficits in myelin ultrastructure, white matter, axonal conductivity, and motor skills. Last, we observed significant impairments, with clinical relevance, in induced pluripotent stem cell-derived OLs from a patient with the InsG3680 mutation. Together, our study provides insight into Shank3’s role in OLs and reveals a mechanism of the crucial connection of myelination to ASD pathology
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