Summary: The autism-linked Gabrb3 gene appears to shape the formation of normal and atypical neural connections in the brain.
Source: Cornell University
A gene linked to autism spectrum disorders plays a critical role in early brain development and may shape the formation of normal and atypical nerve connections in the brain, according to a new study from Weill Cornell Medicine researchers.
The study, published November 28 in neuron, used a combination of sophisticated genetic experiments in mice and analyzes of human brain imaging data to better understand why mutations in a gene called Gabrb3 are linked to a high risk of developing autism spectrum disorder ( ASD) and a related condition called Angelman Syndrome. Both conditions involve abnormal behaviors and unusual responses to sensory stimuli, which appear to stem, at least in part, from the formation of atypical connections between neurons in the brain.
“Neural connections in the brain and the developmental synchronization of neural networks are disrupted in people with autism spectrum disorders, and there are specific genes implicated in the pathogenesis of ASDs,” said co-first author Dr. Rachel Babij, former Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-Ph.D. program in the lab of Natalia De Marco García, associate professor at the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.
The Gabrb3 gene encodes part of a critical receptor protein found in inhibitory connections in the brain, which compresses neural activity to maintain order in the nervous system, like police officers directing traffic. During development, Gabrb3 also appears to help determine how brain connections are formed.
To understand how Gabrb3 works, Babij and his colleagues tracked cell signaling inside the brains of normal animals and those lacking the gene in early stages of development.
Preclinical experiments, which Babij performed alongside co-first author Camilo Ferrer, postdoctoral associate in the De Marco García lab, and others, revealed that mice lacking Gabrb3 fail to form the normal network of connections between neurons in a specific region of the brain involved in sensory processing.
“It’s not a pervasive problem in which each neuron fails to contact, or contacts inappropriately, its targets; but it’s actually a subset of cells that are more sensitive to this,” said De Marco García, who is the paper’s lead author.
In collaboration with the laboratory of Dr. Theodore Schwartz at Weill Cornell, the authors showed that the net result of Gabrb3 deletion is an increase in functional connections between the two brain hemispheres in genetically modified mice, compared to those with a functional Gabrb3 gene. Genetically modified mice are also hypersensitive to touch.
“Basically what we see is that these neurons are more sensitive to sensory stimuli after this gene is deleted,” said De Marco García.
The team then collaborated with Dr. Conor Liston’s lab at Weill Cornell to examine the role of the gene using neuroimaging data from human subjects. The researchers found a correlation between the spatial distribution of the human GABRB3 gene and atypical nerve connectivity in people with ASD.
“The lower the expression of GABRB3 in specific brain regions, the more likely those regions are to contain atypical nerve connections,” said De Marco García.
While warning that it is impossible to draw direct parallels between preclinical and human data, De Marco García suggests that both analyzes point to a model of neurological disorders in which alterations in genes such as GABRB3 could lead to specific changes. in neural connection patterns, which in turn lead to abnormal behaviors. Interactions between different genes, each with slightly different effects, could produce significantly different results.
Babij agrees. “What causes one person to develop schizophrenia and another to develop ASD, when both have an element of inhibitory neural dysfunction? I think something about the specific subtypes of neurons affected and the mutations that affect them might play into how people develop these different diseases,” she said.
About this ASD and Genetics Research News
Author: Alan Dove
Source: Cornell University
Contact: Alan Dove – Cornell University
Image: The image is credited to Camilo Ferrer
Original research: Access closed.
“Gabrb3 is required for the functional integration of pyramidal neuron subtypes in the somatosensory cortex” by Rachel Babij et al. neuron
Gabrb3 is required for the functional integration of pyramidal neuron subtypes in the somatosensory cortex
- Gabrb3 is necessary for desynchronization of the cortical network in murine S1
- GABAergic disruption results in improved contralateral, but not ipsilateral, connectivity
- Gabrb3 ablation results in increased whisker-dependent responses during mouse development
- Spatial model of man GABRB3 expression correlates with atypical connectivity in ASD
Dysfunction of gamma-aminobutyric acid (GABA)ergic acid circuits is strongly associated with neurodevelopmental disorders. However, the impact of genetic predispositions on circuit assembly is unclear.
Using Direct two-photon, wide-field calcium imaging in developing mice, we show that Gabrb3a gene strongly associated with autism spectrum disorders (ASD) and Angelman syndrome (AS), is enriched in contralateral projection pyramidal neurons and is required for inhibitory function.
We report that Gabrb3 ablation results in decreased development of GABAergic synapses, increased local network synchronization, and sustained improvement in functional connectivity of contralateral, but not ipsilateral, pyramidal neuron subtypes.
In addition, Gabrb3 suppression results in increased cortical response to tactile stimulation in neonatal stages.
Using human transcriptomics and neuroimaging datasets from ASD subjects, we show that the spatial distribution of GABRB3 the expression is correlated with atypical connectivity in these subjects.
Our studies reveal a need for Gabrb3 during the emergence of interhemispheric circuits for sensory processing.
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