Researches create mini-brain model of idiopathic ASD characterized by early neuronal proliferation -
The vast majority of cases of autism spectrum disorders (ASD) are idiopathic - the cause is unknown. In an article published this month in the journal Molecular Psychiatry , researchers at the University of California at San Diego School of Medicine, with colleagues across the country and around the world, created a model of "mini-brain", derived from people with a particular form of idiopathic ASD characterized by oversized brains, revealing a molecular pathway defective in brain development resulting in early neuronal proliferation and dysfunctional cortical networks.
"The key is that we can now effectively idiopathic ASD model using a cohort of individuals selected by a clear endophenotype. in this case, the volume of the brain, "said lead author Alysson R. Muotri, PhD, associate professor at UC San Diego School of Medicine Departments of Pediatrics and Cellular and Molecular Medicine. "And brain development early expansion can be explained through molecular and cellular dysregulation underlying, leading to cortical neuronal networks altered."
The characteristics and causes of ASD are diverse and not fully known - facts that made it difficult to fully discover the genetic, pathological and relevant cell that could be widely shared. A separate pathophysiology or a messy process is the appearance of macrencephaly in some children with ASD, which is characterized by the early neuronal proliferation and brain abnormally dilated. Macrencephaly occurs during the first three years of life and before the first clinical signs of ASD. About 20 percent of people with autism have macrencephaly.
The researchers reasoned that autistic people macrencephaly probably shared an underlying molecular and cellular pathology. They created neural progenitor cells programmed from induced pluripotent stem cells from children with ASD.
"By sequencing the genome, we realized that some, but not all were clear changes in the Wnt way, which is a molecular pathway previously implicated in cancer," says Muotri. "the defects in the cell cycle control were also evident of gene expression on these cells. As a result, neural progenitor cells derived from children proliferate faster than controls, which explains the large phenotype of the brain. "
Next, the researchers differentiated progenitor cells in cortical neural networks, main type of functional cell of the brain cortex (gray matter).
"We have shown that ASD networks fail to produce inhibitory neurons and found that several receptors and GABA-related neurotransmitters (a amino acid that acts as a neurotransmitter) are misregulated on these neurons. We have also shown that the number of excitatory synapses is reduced, which leads to malfunctions when we analyzed the maturation of neural networks in time. in fact, we detected a lack of synchronization burst (when multiple neurons simultaneously draw).
Finally, the research team tested a drug already in clinical trials (IGF-1) in a cohort of study participants, saying it caused a reversal of neuronal damage, although that the degree of response varied ASD individual.
Muotri said the results show that it is possible to stratify autism more effectively for clinical trials by identifying individuals who are likely to be more sensitive to specific therapies using their "mini -brains "in a dish.
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