How brain cells restore healthy growth and connections after a disease-causing genetic deletion

by John Pastor, Virginia Tech

edited by Lisa Lock, reviewed by Robert Egan

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Scientists at Virginia Tech's Fralin Biomedical Research Institute at VTC have discovered how an experimental therapy can help brain cells overcome the effects of a disease-causing genetic deletion. Instead of repairing the deletion and its immediate consequences, the therapy redirects brain development by helping at-risk neurons grow and connect more normally.

The findings, published in Disease Models & Mechanisms, suggest that some genetic brain disorders may be treated by targeting the cellular mechanisms disrupted by a genetic change rather than repairing the genetic change itself.

Oxidative stress as a target

The research focused on 22q11.2 deletion syndrome, the second most common genetic deletion disorder and among the strongest known genetic risk factors for schizophrenia in humans. The syndrome affects approximately 1 in every 2,000 to 4,000 births and is also associated with autism spectrum disorder and a range of cognitive and developmental challenges.

Using a mouse model of 22q11.2 deletion syndrome, the researchers identified oxidative stress—a buildup of harmful oxygen-containing molecules inside brain cells—as a key contributor to abnormal brain development.

They then treated mice with N-acetylcysteine (NAC), an antioxidant that effectively crosses the blood-brain barrier, to determine whether reducing that stress could restore healthy growth and connectivity.

The treatment improved the health of mitochondria, strengthened connections between neurons and restored the growth of dendrites—the branch-like extensions on neurons that receive synaptic signals from other neurons, mediating communication within the brain's neural networks.

An alternate genetic route

"Think of it as a detour around a network of winding roads where several trees have fallen," said Anthony-Samuel LaMantia, professor at the Fralin Biomedical Research Institute at VTC and the study's corresponding author. "The detour still gets you to your destination even though the original route remains blocked. In this case, the therapy activates a different set of genes that helps neurons form functional brain circuits despite the genetic deletion."

The researchers discovered that the therapy did not restore the activity of genes disrupted by the deletion. Instead, it activated a different network of genes that enabled neurons to achieve many of the same developmental results.

"That was surprising because the assumption behind most therapies is that you have to restore gene expression to its normal ground state," said LaMantia, director of the institute's Center for Neurobiology Research. "Our findings suggest that may not always be possible or even necessary. There can be therapeutic benefits from taking an alternate route."

Stronger circuits, better behavior

The study also helps explain why the therapy improves brain function. Rather than replacing lost neurons, the treatment strengthened the connections among the neurons that remained, restoring the cumulative strength of communication signals within brain circuits that underlie learning and cognitive flexibility.

In the mouse model, these improvements were accompanied by better performance on behavioral tasks that depend on those circuits.

Although additional research will be needed before the findings can be translated into human therapies, the study points to a new way of thinking about treatments for genetic brain disorders, LaMantia said. Rather than trying to correct every disrupted gene or molecular pathway, researchers may be able to harness the natural ability of gene networks to help brain cells develop more normally.

"Gene networks are remarkably flexible," LaMantia added. "We may be able to develop therapies that engage that flexibility instead of trying to correct a specific genetic or molecular disruption that may be too difficult to manipulate directly."

Publication details

Shah Rukh et al, An antioxidant therapy elicits distinct transcriptome responses in 22q11-deleted upper layer cortical projection neurons, Disease Models & Mechanisms (2026). DOI: 10.1242/dmm.052786

Journal information: Disease Models & Mechanisms

Key medical concepts

22q11.2 deletion syndromeOxidative StressAcetylcysteineMitochondriaDendrites

Clinical categories

NeurologyClinical genetics Provided by Virginia Tech Who's behind this story?

Lisa Lock

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