November 18, 2021


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Tags: Autism, define, hyperconnectivity, overgrowth, Spectrum, subtype, synaptic


Categories: autism

Synaptic overgrowth, hyperconnectivity could outline autism subtype | Spectrum

Group Theory: A subset of autistic people have an over-connectivity signature of the brain, which can result from an excess of synapses.

Courtesy of Alessandro Gozzi

A form of autism characterized by a characteristic pattern of over-connectivity in the brain arises from an excess of synapses, according to a new study in mice. The results support the theory that autism subtypes have different biological roots and may require different approaches to treatment.

Autistic people have altered brain connectivity, as previous work suggests, although it was unclear whether the strength of connections is increased or decreased compared to non-autistic people and where – or even why – the differences occur.

According to a study published earlier this year, different mouse models of autism exhibit different patterns of brain connectivity, a finding that could explain some of the inconsistencies seen in humans. But the research group around Alessandro Gozzi, Senior Researcher at the Istituto Italiano di Tecnologia in Rovereto, Italy, wanted to go one step further.

“We noticed that there are different signatures,” says Gozzi. “And now we’re trying to decipher it.”

For the new study, Gozzi and his colleagues examined the brain connectivity of mice that lacked a copy of the TSC2 gene. These mice model the complex of tuberous sclerosis, a condition that is often accompanied by autism. TSC2 typically acts as a brake on the mTOR signaling pathway, which is involved in cell growth and proliferation. Damaging mutations in the gene lead to overactivity of the signaling pathway and an abundance of synapses throughout the brain, as previous studies have shown.

The new work suggests that mTOR overactivity and the resulting excess of synapses causes a specific pattern of brain hyperconnectivity that is observed in some autistic people. The results were published in Nature Communications in October.

Connection points:

Gozzi and colleagues used functional magnetic resonance imaging (fMRI) to map synchronous activity in the brains of TSC2 mice. It is assumed that areas that are activated or deactivated synchronously are connected in a circuit.

Compared to wild-type mice, the TSC2-deficient mice show hyperconnectivity in a circuit that includes the prefrontal cortex, the islet cortex and the striatum – three brain areas that are involved in autism.

The TSC2 animals had no atypical white matter structure or other visible changes in the brain that could explain this difference in connectivity. But they had an increased density of dendritic thorns, the nodes at which a neuron receives signals from other neurons, found Gozzi and his colleagues. Increased spine density also occurs in the brains of some autistic people.

The animals’ hyperconnectivity disappeared after the researchers treated the mice with rapamycin, a drug that inhibits the mTOR signaling pathway. And the treated mice no longer showed repeated grooming or decreased sociability, a behavior that was reminiscent of that of people with autism.

“It implies these extra synapses in that hyperconnectivity signature,” Gozzi says.

The same hyperconnectivity signature occurs in a subset of autistic people that Gozzi and his colleagues found using anonymized fMRI data from the Autism Brain Imaging Data Exchange (ABIDE). The most closely linked regions in this subgroup also express a disproportionate number of genes that have been linked to autism and that can interact with mTOR or TSC2 proteins.

The team also identified other connectivity signatures among the scans. One group of autistic people showed widespread sub-connectivity and another group showed weak frontal hyperconnectivity.

Signature style:

“These are very first steps, but very important steps,” says David Sulzer, a professor of psychiatry, neurology and pharmacology at Columbia University who was not involved in the study.

“It’s an important building block in an overall movement to understand what autism really is [and] why it’s developing, ”he says. “Everything points to problems with normal brain maturation,” such as the lack of synaptic pruning that occurs when the mTOR pathway is not controlled.

The TSC-deficient mice are not an ideal model for autism because not all people who are missing a copy of the gene are autistic, says Peter Crino, professor and chair of neurology at the University of Maryland at Baltimore, who is not at work was involved.

A better approach might be to genetically modify the mice to carry human variants of the gene known to be linked to the autism brain. “

But for now, the results suggest that inhibition of the mTOR pathway is a potential treatment for at least a subset of autistic people, say Crino and Sulzer.

Gozzi and colleagues plan to investigate whether any of the other signatures of atypical connectivity – which can represent different subtypes of autism – can be linked to other changes in biology.

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