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Autism in males linked to defect in brain immune cells, microglia

Many cases of autism spectrum disorders (ASDs) may result from problems in immune cells that normally work to trim back unneeded brain connections in early life.

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Photo by Anna Kolosyuk from Unsplash.com

Many cases of autism spectrum disorders (ASDs) may result from problems in immune cells that normally work to trim back unneeded brain connections in early life, suggests a new study led by scientists at Scripps Research.

The study, published in Nature Communications, examined the effects of a set of gene mutations that account for a small percentage of autism disorders. These mutations are known to cause a general overproduction of many proteins in brain cells, but how that overproduction leads to autism behaviors has been a mystery.

The scientists found evidence that the most relevant effect of this protein overproduction occurs in brain-based immune cells called microglial cells. These cells normally prune unneeded brain connections, or synapses, as the brain develops in childhood.

Working in mice, the scientists determined that the protein overproduction impairs microglial cells in a way that hampers their synapse-pruning function, but only in males, leading to autism-like social behavior deficits.

The finding dovetails with the long-standing observation that autism disorders are four to five times more prevalent in males than females. It is also consistent with recent evidence that in people with ASDs, the brain commonly has a higher number of synapses than normal.

“Our study suggests that impairments in microglia play a key role in the development of autism behaviors, at least in some cases, and may help explain the higher prevalence of autism disorders in males,” says study senior author Baoji Xu, PhD, professor in the Department of Neuroscience at Scripps Research. “That, in turn, suggests that microglia might be a good target for future drugs that prevent or treat autism spectrum disorders.”

ASDs are found in an estimated 2.4 percent of boys and 0.5 percent of girls. They involve a variety of abnormalities including social skill deficits, repetitive behaviors, and hypersensitivities to sounds and light. Research suggests that these disorders are largely genetic but can be caused by abnormalities in a variety of different genes acting alone or in combination. To date, well over 100 gene mutations and variants have been linked to ASDs.

One set of autism-linked gene abnormalities–which include mutations in the genes PTEN, TSC1, TSC2, and FMR1–accounts for about 3 percent of ASD cases. The common effect of these abnormalities is to disrupt a pathway that normally regulates the level of protein production in cells, allowing protein production to rise.

Xu and his team sought to determine if there is a particular cell type in the brain that explains the connection between elevated protein production and ASD-like behaviors. They engineered mice to make–in just one cell type at a time–abnormally high levels of a protein-production factor called eIF4E. A high level of eIF4E is thought to be one of the common events that links PTEN, TSC1 and other autism mutations that increase protein production.

The team found that when high eIF4E levels occurred in microglial cells, the mice developed ASD-like abnormalities in social behavior, as well as cognitive deficits and repetitive behaviors. Curiously, although protein production rose in the microglial cells of both male and female mice, the ASD-type abnormalities occurred only in male mice.

The same behavioral abnormalities were not seen at all when the high eIF4E levels occurred in neurons or in helper cells called astrocytes, although mice whose neurons had high eIF4E levels showed more anxiety-like behaviors.

The researchers examined affected microglial cells for clues to how elevated protein synthesis in these cells could lead to ASD-like behavioral changes. They found that in young male mice, microglial cells in important brain regions, including the medial prefrontal cortex, the hippocampus and the striatum, were significantly larger and also more numerous, whereas in females these changes were much more subtle and transient.

Microglia during brain development normally prune synapses that are unused or otherwise unwanted. Xu and his colleagues found that in the male ASD-like mice with elevated microglial eIF4E, there were more synapses than normal, suggesting a pruning deficit–a pattern also thought to be widely present in people with autism.

The affected microglia in the mice showed gene activity patterns indicating an enhanced capacity to prune synapses. However, experiments also revealed that the cells lacked the usual motility, or movement ability, that would enable them to carry out their synapse pruning functions. Xu and his colleagues suspect that this reduction in microglial motility may be the most important factor, so that on balance the cells’ synapse-pruning abilities are impaired, leading to ASD-like brain changes.

The researchers now are following up with studies to discover precisely why protein increases affect microglia in males so much more than in females. That discovery could prove to be an important piece of the puzzle of sex differences in autism–and could suggest new targets for autism treatments.

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Beauty & Fashion

Redefining aesthetics: From anti-aging to healthy aging

Growing attention is now being given to healthy aging, understanding how the entire face changes over time, preserving facial harmony, and helping people continue to look like themselves.

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For decades, “anti-aging” has defined the beauty and aesthetics conversation, promising to erase wrinkles and reverse the signs of time. Today, that conversation is shifting.

Aging is no longer just about looking younger. Growing attention is now being given to healthy aging, understanding how the entire face changes over time, preserving facial harmony, and helping people continue to look like themselves.

A review published in Facial Plastic Surgery, The Anatomy of the Aging Face: A Review, describes aging as changes across bone, ligaments, muscles, fat, and skin. Another review in Aesthetic Surgery Journal, The Facial Aging Process From the “Inside Out”, explains how changes beneath the surface eventually become visible on top.

Studies in Plastic and Reconstructive Surgery show facial fat is organized into distinct anatomical compartments that can lose volume and shift position over time, altering facial shape and balance.

For multi-awarded aesthetic physician Dr. James Co, founder of Cosma Institute and Architect of Aesthetic Confidence, these findings are the reason aesthetic care must start with understanding, not just treating.

“Aging is not a disease we need to cure,” Co said. “It is a biological process. As physicians, our role is to understand what is changing beneath the surface, how those changes differ from person to person, and whether intervention is appropriate in the first place.”

“When you only look at the wrinkle, you are looking at the surface of a much bigger anatomical process,” he added. “The face ages as a system. Good assessment means understanding what is happening underneath before deciding what should be done on the surface.”

Part of that understanding is recognizing that no two faces age the same way. Two people can be the same age and experience aging very differently. Genetics, skeletal structure, fat distribution, skin characteristics, sun exposure, lifestyle, and environmental factors all influence how aging presents.

“Two patients can be the same age and come to me with completely different anatomy, lifestyles, concerns, and goals,” Co said. “Why would we expect their treatment plans to look exactly the same?”

This is where healthy aging broadens the conversation — from fixing isolated signs to looking at the face as a whole and listening to what the individual actually wants.

“Someone can want to look refreshed without wanting to look 20 years younger,” Co said. “Those are completely different goals.”

Rather than trying to freeze one version of the face forever, healthy aging acknowledges that the face will continue to change. As different structures change at different rates, the relationship between features evolves. Facial harmony is therefore not fixed.

“You cannot freeze one version of your face forever,” Co said. “But you can understand how the face is changing and make decisions that respect its natural proportions and your identity.”

In the age of social media, where aesthetic treatments are highly visible, Co cautions against self-diagnosis.

“Patients should not have to diagnose themselves from social media,” he said. “You might recognize a concern, but deciding why it is happening and what should be done about it requires proper assessment.”

The shift is also about how people feel, not just how they look. A 2022 review on minimally invasive facial aesthetic procedures found studies are increasingly looking beyond physical changes to include satisfaction with appearance and aspects of psychological and social well-being, while noting that evidence still needs careful interpretation.

For Co, this reinforces that success is not always about looking dramatically younger.

“We need to ask whether the result makes sense for the patient, whether expectations were met, and whether we preserved the things that make that person recognizable,” he said. “I would rather someone tell my patient, ‘You look well,’ than immediately ask, ‘What did you have done?'”

At Cosma Institute, Co applies this consultation-led philosophy through individualized assessment, facial harmony, medical judgment, and patient education. Having trained aesthetic practitioners across Southeast Asia and Europe, he advocates for natural-looking outcomes that respect the characteristics already present in each face — an approach that recently earned him two awards at the Merz Aesthetics Tala Awards.

For Co, the evolution of aesthetic medicine is not about having more tools, but knowing when to use them — and when not to.

“Aging cannot be stopped, and I don’t think that should be the promise,” he said. “What we can do is understand it better. We can look at the science, understand the anatomy, listen to the patient, and make decisions that allow them to age while still looking recognizably like themselves.”

For Co, healthy aging begins not with fighting age, but with understanding it.

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The look and feel of your neighborhood may affect your sleep

Those living in neighborhoods rated as having a stronger sense of safety tended to sleep longer, and that this rating appeared to be shaped by the streetscape.

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Your neighborhood’s “streetscape”—the physical environment of your street—is something that you have probably never consciously thought about, despite seeing it every day. But what if the streetscape was affecting you on a subconscious level and disrupting your sleep? 

This intriguing question is posed by the findings of a study led by Professor Daisuke Matsushita of the Graduate School of Human Life and Ecology at Osaka Metropolitan University. The research team used AI to analyze more than 200,000 Google Street View images to identify visual neighborhood characteristics. They then linked these characteristics to the self-reported sleep of 1,089 working adults living on the lower floors of apartments in Tokyo, who were most likely to be affected by the streetscape.  

They found that those living in neighborhoods rated as having a stronger sense of safety tended to sleep longer, and that this rating appeared to be shaped by the streetscape. Generally, people slept longer in areas with lots of greenery, such as leafy trees, on the street. Similarly, high “enclosure”—meaning many tall vertical buildings and few wide-open spaces—was also associated with longer sleep and fewer insomnia symptoms. 

However, the study also made a surprising finding. The researchers found that highly walkable streetscapes, such as those with more sidewalks and traffic signs, were associated with a lowered sense of safety and shortened sleep duration.  

This suggests that walkability does not always represent a reassuring environment. Instead, a possible explanation is that streets with extensive pedestrian infrastructure are often busier, more crowded, and used by more strangers, which may be perceived as less safe or less relaxing than quieter residential streets.  

“This study demonstrates the potential for evaluating streetscape characteristics across large geographic areas in a cost-effective manner,” Dr. Matsushita said. “Based on the technique used in this study, cities could potentially measure perceived safety, beauty, liveliness, and enclosure as well as pollution and noise.”  

“We hope that opening up this new perspective creates further possibilities for designing healthier neighborhoods,” he concludes.  

The findings were published in Building and Environment.

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Workout or nap? Either can help your sleepless brain, study finds

People who either completed 20 minutes of moderate-to-vigorous exercise or took a 90-minute nap performed about 22 per cent better on memory tests after 30 hours without sleep than those who did neither.

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A short workout or a nap can help protect memory after a sleepless night, a McGill University-led study has found.

Researchers found people who either completed 20 minutes of moderate-to-vigorous exercise or took a 90-minute nap performed about 22 per cent better on memory tests after 30 hours without sleep than those who did neither. The findings, published in Proceedings of the National Academy of Sciences (PNAS), point to practical ways to counter the effects of sleep deprivation.

“Sleep loss affects nearly every aspect of how we think and function, but many people can’t simply stop what they’re doing and get more sleep,” said senior author Marc Roig, Professor in McGill’s School of Physical and Occupational Therapy. “Our findings show that even a brief bout of exercise may help preserve one of our most important cognitive abilities.”

The study involved 54 healthy young adults who stayed awake for 30 consecutive hours under lab supervision. Participants were then assigned to one of three groups: a 20-minute cycling session, a 90-minute nap or a control condition. Three days later, researchers tested their memory for images they had viewed immediately after the intervention. Those who exercised or napped remembered significantly more images than participants who did neither.

Same result, different pathways

While the memory benefits were nearly identical, brain recordings revealed that exercise and napping helped in different ways.

Napping appeared to help the brain recharge, making it easier to take in and remember new information. Exercise, by contrast, helped the brain use its remaining resources more efficiently, without making participants feel more tired.

The findings could eventually inform fatigue-management strategies in workplaces where sleep loss is common and mistakes can have serious consequences, such as health care, transportation and emergency response.

“A nap isn’t always possible in the middle of a shift,” said first author Madhura Lotlikar, a doctoral candidate in McGill’s Department of Neurology and Neurosurgery. “Exercise is accessible, inexpensive and easy to implement. That makes it a promising tool to help people stay cognitively sharp when sleep is limited.”

The researchers emphasize that exercise cannot replace sleep, but it may help people function better when getting enough rest isn’t possible.

About the study

“Protecting episodic memory after sleep loss: Similar benefits of exercise and naps via distinct neural contributions” by Madhura Lotlikar and Marc Roig et al., was published in Proceedings of the National Academy of Sciences of the United States of America.

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