Overview: The Gabrb3 gene linked to autism appears to shape the formation of both 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 both normal and atypical nerve connections in the brain, according to a new study by researchers at Weill Cornell Medicine.
The study, published Nov. 28 in neuron, used a combination of advanced genetic experiments in mice and analysis 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 behavior and unusual responses to sensory stimuli, which appear to arise, at least in part, from the formation of atypical connections between neurons in the brain.
“Neuronal connections in the brain and developmental synchronization of neuronal networks are disrupted in individuals with autism spectrum disorders, and there are specific genes involved in the pathogenesis of ASD,” said co-first author Dr. Rachel Babij, a former student at Weill Cornell. /Rockefeller/Sloan Kettering Tri-Institutional MD-Ph.D. program in the lab of Natalia De Marco García, an associate professor at Weill Cornell Medicine’s Feil Family Brain and Mind Research Institute.
The Gabrb3 gene encodes part of a crucial receptor protein found in inhibitory compounds in the brain that suppress neuronal activity to maintain order in the nervous system, such as police officers directing traffic. During development, Gabrb3 also appears to help determine how brain connections form.
To find out how Gabrb3 works, Babij and her colleagues tracked cellular signaling in the brains of both normal animals and those without the gene in the early stages of their development.
The preclinical experiments, conducted by Babij with co-first author Camilo Ferrer, a postdoctoral fellow in the De Marco García lab, and others, showed that mice lacking Gabrb3 fail to maintain the normal network of connections between neurons in a specific brain region involved in sensory processing.
“It’s not a ubiquitous problem where every single neuron won’t or inappropriately contact their targets; but it’s actually a subset of cells that are more sensitive to it,” says De Marco García, the paper’s lead author.
In collaboration with the laboratory of Dr. Theodore Schwartz in Weill Cornell, the authors showed that the net result of Gabrb3 deletion is an increase in functional connections between the two hemispheres in the genetically modified mice, compared to those with a functional Gabrb3 gene. The genetically modified mice are also hypersensitive to touch.
“Basically, what we see is that these neurons respond better to sensory stimuli after deletion of this gene,” said De Marco García.
The team then collaborated with Dr. Conor Liston at Weill Cornell to investigate the gene’s role 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 atypical nerve connections these regions are likely to contain,” said De Marco García.
While warning that it is impossible to draw direct parallels between the preclinical and human data, De Marco García suggests that both analyzes point to a model of neurological disease in which changes in genes such as GABRB3 could cause specific changes in neuronal connectivity patterns, which in lead to abnormal behavior. Interactions between different genes, each with slightly different effects, can produce substantially different outcomes.
Baby agrees. “What causes one person to develop schizophrenia while the other person develops ASD, when both have an element of inhibitory neuron dysfunction? I think something about the specific subtypes of affected neurons and the mutations that affect them could play a role in how people develop these different diseases,” she said.
About this news about ASD and genetic research
Original research: Closed access.
“Gabrb3 is required for the functional integration of pyramidal neuron subtypes in the somatosensory cortexby 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 enhanced contralateral, but not ipsilateral connectivity
- Gabrb3 ablation leads to increased whisker-dependent responses during mouse development
- Spatial pattern of man GABRB3 expression correlates with atypical connectivity in ASD
Dysfunction of gamma-aminobutyric acid (GABA)ergic circuits is strongly associated with neurodevelopmental disorders. However, it is unclear how genetic predisposition affects circuit assembly.
Using empathize two-photon imaging and wide-field calcium in developing mice, we show Gabrb3a gene strongly associated with autism spectrum disorder (ASD) and Angelman syndrome (AS), is enriched in contralaterally projecting pyramidal neurons and is required for inhibitory function.
We report that Gabrb3 ablation leads to a developmental decrease in GABAergic synapses, increased local network synchronization, and long-term improvement in the functional connectivity of contralateral – but not ipsilateral – pyramidal neuron subtypes.
In addition, Gabrb3 deletion leads to an increased cortical response to tactile stimulation in neonatal stages.
Using human transcriptomics and neuroimaging datasets of ASD subjects, we show that the spatial distribution of GABRB3 expression correlates with atypical connectivity in these subjects.
Our research shows that there is a need for Gabrb3 during the emergence of interhemispheric circuits for sensory processing.