Summary: Researchers have created “mini-brains” using stem cells from people with a unique form of autism, allowing them to study brain development in depth. These organoids demonstrated how dementia is caused by a genetic mutation in MEF2C that disrupts the balance between excitatory and inhibitory synapses.
The study also found that an experimental medication, NitroSynapsin, can partly correct this imbalance in the organoids, offering desire for new dementia solutions. This study demonstrates how brains organoids may aid in the development of potential treatments for autism spectrum disorder.
Important Facts:
- ” Mini-brains” created from stem cells show how MEF2C abnormalities cause autism.
- NitroSynapsin restored nerve stability in brain organoids, showing therapy possible.
- Research provides insight into novel treatment options for autism spectrum disorder.
Origin: Scripps Research Institute
Researchers at Scripps Research have developed personalized “mini-brains” ( or organoids ) to study the disorder in new detail using stem cells from patients with a uncommon and severe form of autism spectrum disorder and intellectual disability.
The group now has a better understanding of how one biological gene causes autism spectrum disorder as a result of the lab-grown organoids. It also showed that an , empirical substance, called NitroSynapsin, reversed some of the , head dysfunction , associated with autism in these designs.
” Our work shows how this biological gene that has been associated with autism, disrupts the normal balance of brain cells during advancement”, says Stuart A. Lipton, MD, Ph. D., Step Family Foundation Endowed Professor and co-director of the Neurodegeneration New Medicines Center at Scripps Research, a scientific physician, and older author of the new study published online in , Molecular Psychiatry , on September 30, 2024.
However, we’ve even established that this imbalance might be addressed in the future.
Learning from people
Autism spectrum disorder ( ASD ) is a neurological and developmental disorder that affects social interactions, repetitive interests and behaviors, and communication. A number of genetic variations have been linked to the problem, but each of the reasons merely half understands how many cases are caused by ASD.
Reports of ASD have focused for many years on modeling the problem in animals or studying isolated people brain tissue. No one can completely recreate the richness of a human head that is interconnected.
Lipton and his colleagues focused on MEF2C haploinsufficiency syndrome ( MHS), a rare and severe form of ASD and , intellectual disability , caused by a genetic variation in the MEF2C gene.
They used , body cells , isolated from people with MHS and used present stem cell biology approaches to transform those organisms into human , stem cells, and then grew them into small, millimeter-sized “mini-brain” organoids in which the experts could analyze how the various types of brain cells communicate with each other.
” We was breed important aspects of the brains of people to study their , electronic activity , and other parameters”, says Lipton.
” We actually brought kids into the lab to see their own mini-brains,” according to the parents.
In healthy human brains and brain organoids, neural stem cells develop into , nerve cells , ( or neurons ), which send and receive messages throughout the brain, as well as into various types of glial cells, which are supportive cells recently shown to be important in signaling and in immune function.
Healthy brains have a balance of inhibitory and regenerative neurons that inhibit electrical signaling. Autism causes an excitatory/inhibitory imbalance, often resulting in too much excitation.
In the organoids developed from the cells of children with MHS, the , neural stem cells , more often developed into glial cells, causing a disproportionate number of glial cells compared to neurons, Lipton’s group found. In particular, the MHS organoids had fewer inhibitory neurons than usual. Similar to many real human brains with ASD, this caused excessive electrical signaling in the minibrains.
A role for microRNA
Nearly 200 genes were directly controlled by the MEF2C gene when Lipton’s team examined exactly how MEF2C mutations could cause this imbalance between cell types. They encoded genes for microRNA molecules, which stands out among the rest of these genes because they did not encode the DNA that caused messenger ( m ) RNA and protein expression.
MicroRNAs ( miRNAs ) are small RNA molecules that, rather than producing proteins themselves, bind to DNA to control gene expression. For their research describing the discovery of miRNA molecules and how they can affect cell development and behavior, two scientists received the 2024 Nobel Prize in Physiology or Medicine this month.
” In our study, a few specific miRNAs appear to be important in telling developing brain cells whether to become glial cells, excitatory neurons, or inhibitory neurons”, says Lipton.
The development of the brain is preventing the creation of proper nerve cells and proper connections or synapses between nerve cells because of mutations in MEFC2.
Early, developing brain cells from patients with MHS, Lipton’s group found, have lower levels of three specific miRNAs. When the researchers added extra copies of these miRNA molecules to the patient-derived brain organoids, the mini-brains developed more normally, with a standard balance of neurons and glial cells.
A potential treatment
Treatments that aim to alter initial development, such as the correction of a mutated gene or the addition of miRNA molecules to stop the imbalance of cell types, are currently not feasible because ASD is typically not recognized during fetal brain development.
However, even after developing, Lipton was already working on a new drug to support the maintenance of the balance between excitatory and inhibitory neurons.
Lipton’s group recently tested such a drug, which he and colleagues invented and patented under the name NitroSynapsin (aka EM-036), for , its ability to restore brain connections , in “mini-brains” made from cells affected by Alzheimer’s disease.
They examined whether the drug could also be used to treat the MHS form of autism in the new paper. Lipton and his colleagues demonstrated that NitroSynapsin, a neuronal imbalance that was partially corrected by using patient-derived brain organoids, prevented the mini-brain from exhibiting hyperexcitability and restores the excitatory/inhibitory balance in fully developed brain organoids. Additionally, it shielded the connections or synapses between nerve cells.
More research is required to determine whether the medication improves MHS symptoms or whether it affects other types of autism spectrum disorder that are not the result of MEF2C gene mutations. According to Lipton, he holds the possibility that this is the case because MEF2C is known to have an impact on many other genes linked to autism.
With the goal of getting this drug into people in the near future, Lipton says,” We are continuing to test this drug in animal models.” ” This is an exciting step in that direction”.
About this news about autism and genetics
Author: Stuart A. Lipton
Source: Scripps Research Institute
Contact: Stuart A. Lipton – Scripps Research Institute
Image: The image is credited to Neuroscience News
Original Research: Open access.
” In MEF2C autism patients with hiPSC-neurons and cerebral organoids, miRNA expression and excitation are dysregulated.” by Stuart A. Lipton et al. Molecular Psychiatry
Abstract
In MEF2C autism patients with hiPSC-neurons and cerebral organoids, miRNA expression and excitation are dysregulated.
MEF2C is a critical transcription factor in neurodevelopment, whose loss-of-function mutation in humans results in MEF2C haploinsufficiency syndrome ( MHS), a severe form of autism spectrum disorder ( ASD ) /intellectual disability ( ID ).
Despite prior animal studies of , MEF2C , heterozygosity to mimic MHS, MHS-specific mutations have not been investigated previously, particularly in a human context as hiPSCs afford.
Here, for the first time, we use patient hiPSC-derived cerebrocortical neurons and cerebral organoids to characterize MHS deficits. Unexpectedly, we found that decreased neurogenesis was accompanied by activation of a micro- ( mi ) RNA-mediated gliogenesis pathway.
We also demonstrate network-level hyperexcitability in MHS neurons, as evidenced by excessive synaptic and extrasynaptic activity contributing to excitatory/inhibitory ( E/I ) imbalance.
Notably, the predominantly extrasynaptic ( e ) NMDA receptor antagonist, NitroSynapsin, corrects this aberrant electrical activity associated with abnormal phenotypes.
During neurodevelopment, MEF2C regulates many ASD-associated gene networks, suggesting that treatment of MHS deficits may possibly help other forms of ASD as well.
