Brain connectivity shift across puberty may explain autism risk in 22q11.2 deletion syndrome

A new study published in Science Advances sheds light on how changes in brain connections before and after puberty might explain why some children with a rare genetic condition called 22q11.2 deletion syndrome have a higher risk of autism and schizophrenia. The findings point to the powerful role that puberty plays in reshaping brain connectivity and hint at molecular factors that drive this process.

22q11.2 deletion syndrome is a genetic condition caused by the loss of a small piece of DNA from the long arm of chromosome 22. This tiny deletion affects roughly 1 in 3,000 to 6,000 births and is one of the strongest known genetic risk factors for a range of developmental and psychiatric disorders. Individuals with this syndrome can experience heart defects, learning disabilities, and delays in speech and motor skills, as well as an increased risk for conditions like autism and schizophrenia. The syndrome is highly variable — some people have mild symptoms, while others face more significant medical and behavioral challenges throughout their lives.

Autism is a neurodevelopmental condition that affects how people perceive the world and interact with others. It is marked by differences in social communication, behavior, and sensory processing. Autism has many causes, including both genetic and environmental factors, making it a complex and diverse condition. Researchers have long tried to understand how changes in the brain, especially in how different areas connect and communicate, relate to the traits and challenges associated with autism.

The new study aimed to shed light on how 22q11.2 deletion syndrome affects brain connectivity and its role in increasing the risk for autism and schizophrenia. The scientists were interested in understanding how connections in the brain evolve across puberty, a critical developmental window when many psychiatric illnesses emerge.

“My lab is interested in why and how brain regions lose their ability to communicate properly. We chose to study 22q11.2 deletion syndrome because it’s both common and uniquely suited to bridge human data and animal models,” said study author Alessandro Gozzi, a senior scientist and director of the Functional Neuroimaging Laboratory at the Italian Institute of Technology.

By using a mouse model of the syndrome alongside brain scans from human participants, the researchers hoped to trace when and where these connectivity changes occur and link them to underlying cellular and molecular events. Their goal was to gain a clearer picture of why certain people with 22q11.2 deletion syndrome are more susceptible to autism and other psychiatric conditions, opening the door for more targeted treatments and earlier interventions.

In their mouse model, called the LgDel mouse, they used brain scans before and after puberty to track changes in connectivity across brain regions. At a younger, prepubertal age, the mouse brains showed widespread hyperconnectivity — too many connections between brain regions. As the mice matured and passed through puberty, this pattern changed, with certain areas, such as the hippocampus, becoming under-connected.

The research team also looked closely at the structure of the brain, focusing on tiny protrusions called dendritic spines, which connect neurons and help with information flow. In juvenile LgDel mice, these spines were too dense, suggesting too many connections between neurons. By adulthood, spine density had decreased sharply, aligning with the drop in connectivity seen in the brain scans. This shift suggested that changes at the level of the synapse, where neurons communicate, could drive the changes in brain connectivity.

One molecular culprit that emerged was an enzyme called GSK3β. In LgDel mice, this enzyme was overactive and linked to abnormal spine densities and brain connectivity. To test this, the researchers treated juvenile mice with a GSK3β inhibitor and found that it normalized both spine densities and connectivity levels. However, this benefit didn’t last into adulthood, suggesting that the timing of treatment may be critical.

Importantly, the researchers found that these changes weren’t just occurring in mice. In brain scans of human carriers of the 22q11.2 deletion, connectivity patterns also evolved across puberty. In childhood, certain brain areas were too connected, while in adolescence and early adulthood, connectivity weakened. These changes aligned with molecular data, highlighting genes associated with synapse structure and function, including those linked to autism.

“We didn’t expect the brain to shift from hyperconnectivity to hypoconnectivity so sharply during development, and even less so to see the same pattern in humans,” Gozzi told PsyPost. “That was a real eye-opener.”

The researchers also found a link between connectivity and behavior. In children with the deletion, increased connectivity in certain sensory and motor areas was associated with higher autism-related traits, while reduced connectivity after puberty appeared related to a shift in these traits.

“Our study shows that brain connectivity problems linked to neurodevelopmental conditions can shift dramatically during adolescence,” Gozzi explained. “Understanding when these changes happen might be just as important as understanding what causes them.”

Although this study provides valuable insights, it has some limitations. The human data didn’t cover every critical point of brain development, making it harder to pinpoint precisely when connectivity shifts occur. Additionally, mouse models can’t capture the full complexity of human behavior and cognition.

“A key limitation is that we didn’t have detailed clinical data in the human cohort, so we couldn’t test whether the connectivity changes we observed actually predict risk for conditions like schizophrenia,” Gozzi noted. “This will be a crucial step for future research.”

Future studies will build on these findings to better understand the molecular changes that drive connectivity across puberty and to explore treatments that might reduce psychiatric risk in people with the 22q11.2 deletion. By linking genes, brain connectivity, and behavior across species, this research brings us closer to understanding how early brain changes can shape long-term mental health outcomes.

“Our next goal is to dig deeper into the biological mechanisms behind this shift and explore whether targeting them (like we did with GSK3β) can prevent long-term brain dysfunction,” Gozzi said. “For me, this study shows how much we can gain by connecting experimental neuroscience with clinical research. The collaboration with Dr. Carrie Bearden was a perfect example of this synergy, and we hope it inspires more bridges between the lab and the clinic.”

The study, “Synaptic-Dependent Developmental Dysconnectivity in 22q11.2 Deletion Syndrome,” was authored by Filomena Grazia Alvino, Silvia Gini, Antea Minetti, Marco Pagani, David Sastre‑Yagüe, Noemi Barsotti, Elizabeth De Guzman, Charles Schleifer, Alexia Stuefer, Leila Kushan, Caterina Montani, Alberto Galbusera, Francesco Papaleo, Wendy R. Kates, Declan Murphy, Michael Vincent Lombardo, Massimo Pasqualetti, Carrie E. Bearden, and Alessandro Gozzi.