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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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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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Could your oral health be affecting fertility?

Chronic oral inflammation may impair female fertility by triggering a systemic immune response that affects the ovaries. A new study shows this leads to oxidative damage, reduced egg quality, disrupted follicle development and reduced live birth rate. These findings point to a potential biological link between oral health and unexplained infertility, opening new directions for future treatments.

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A new study led by Prof. Michael Klutstein at the Hebrew University of Jerusalem and Prof. Asaf Wilensky at the Hebrew University-Hadassah Medical center and spearheaded by the students Dr. Paz Kles and Stephen Ameho has uncovered a striking biological link between chronic oral inflammation and female fertility, suggesting that conditions in the mouth may have far-reaching effects on reproductive health.

Published in the Journal of Dental Research, the study shows that persistent inflammation in the oral cavity can impair ovarian function, reduce egg quality, and ultimately lower fertility rates.

Researchers examined in a mouse model inflammation associated with dental implants, a common clinical scenario, and tracked how immune signals spread throughout the body. Their findings reveal that inflammation does not remain confined to the oral cavity but triggers a systemic immune response that reaches the ovaries.

The consequences were significant. Chronic oral inflammation in the animals was linked to increased levels of inflammatory cytokines in the ovaries, along with shifts in immune cell populations. This was accompanied by oxidative damage to ovarian tissue, impaired development of follicles, and reduced quality of oocytes.

These biological changes translated into measurable reproductive outcomes, with markedly reduced birth rates observed under inflammatory conditions in the animals.

The study also identified deeper cellular effects. Oocytes exhibited DNA damage and epigenetic alterations resembling those seen in reproductive aging, pointing to a possible mechanism by which inflammation accelerates the decline in fertility.

“Inflammation is often thought of as a localized response, but our findings show that it can have systemic consequences that extend as far as the reproductive system,” said Prof. Michael Klutstein. “This work suggests that chronic oral inflammation may be an underrecognized factor in female infertility, potentially contributing to cases that currently have no clear explanation.”

The findings add to growing evidence that oral health is closely linked to overall health. Chronic oral inflammatory conditions such as periodontitis are widespread and have already been associated with a range of systemic diseases.

The researchers note that further investigation in clinical settings will be essential to determine how these findings translate to patient care. If confirmed, the work could open new avenues for diagnosis and treatment, including the use of anti-inflammatory or antioxidant approaches to improve fertility outcomes.

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Maintaining a healthy heart may require regular doses of positivity

The findings of this study further point to the importance of attending to mental and behavioral health for cardiovascular disease prevention and cardiovascular health optimization.

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Positive psychology interventions such as mindfulness, gratitude journaling and optimism training can consistently improve blood pressure, inflammation markers and other cardiovascular disease risk factors within a matter of weeks, a recent study found. However, since these benefits are associated with lifestyle changes such as eating healthier and greater physical activity, the researchers suggested that ongoing reinforcements may be needed to stay on course long term.

Rosalba (Rose) Hernandez, a professor of social work at the University of Illinois Urbana-Champaign, led a team that analyzed the findings of 18 randomized controlled trials that used positive psychological and mindfulness interventions to enhance mental or physical health.

The programs that the team reviewed included individual methods — such as structured telephone sessions, journaling with brief check-ins and digital platforms such as apps and text messaging — and interactive in-person group sessions, as well as hybrid formats that blended these with online tools and virtual meetings. Most of the programs consisted of weekly sessions and at-home activities that reinforced the skills taught, with the majority of programs lasting from six to 12 weeks, the team found.

In general, the programs included 50-200 adults with elevated cardiovascular risk factors such as uncontrolled hypertension, heart failure or other conditions. Typically, the participants were in their late 50s to mid-60s, and women comprised 35-55% of the samples across those studies that reported their participants’ gender, according to the researchers.

“In hypertension and postacute coronary syndrome cohorts, mindfulness-based programs delivered over an eight-week period reduced systolic blood pressure and lowered inflammatory markers such as high-sensitivity C-reactive protein and fibrinogen,” said Hernandez, who is a Fellow of the American Heart Association. “A 12-week spirituality-based digital intervention achieved one of the largest reductions — reducing systolic blood pressure measured with a standard cuff by 7.6 points, and central systolic pressure — which is measured in the aorta as it leaves the heart — by 4.1 points.”

In prior research on positive psychology interventions, scientists seldom defined the dose that was needed to obtain the beneficial effects, Hernandez said. She and the team members sought to clarify the frequency and duration that was most likely to improve individuals’ cardiovascular health.

Programs that had more frequent contact with their participants yielded the most consistent physiological benefits, underscoring the opportunity to embed positive psychological strategies into long-term cardiovascular care, Hernandez said.

The team found that the strongest behavioral improvements were achieved by an eight-week program delivered over WhatsApp that combined weekly sessions with daily microtasks, motivating participants to engage in greater physical activity, eat a healthier diet and take their medication as prescribed. A program that included motivational interviewing succeeded in increasing cardiac patients’ levels of physical activity by 1,800 steps a day and their medication adherence, while the mindfulness programs improved participants’ activity levels and diets only, according to the study.

“The therapeutic dose that was most consistently linked with improvements in blood pressure, inflammation and endothelial function was daily practice reinforced by weekly sessions over eight to 12-week periods,” Hernandez said. “Therapeutic dosing typically involved high-frequency dosing over this time period to obtain short-term physiologic benefits, while ongoing less-intensive contact may be needed to sustain behavioral change.”

Published in the journal Cardiology Clinics, the study was co-written by University of South Florida social work professor Soonhyung Kwon; Alyssa M. Vela, a professor of surgery and of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine; and Katharine S. Edwards, a professor of cardiovascular medicine and of psychiatry and behavioral medicine at Stanford Medicine.

“The findings of this study further point to the importance of attending to mental and behavioral health for cardiovascular disease prevention and cardiovascular health optimization,” Vela said. “This speaks to the need for routine screening and integration of cardiac behavioral medicine to allow for access to important interventions.”

The current study adds to a growing body of research linking psychological well-being — including traits such as optimism, positive affect and gratitude — with cardioprotective benefits.

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Heart disease risk may start in the womb, study finds

Young adults whose mothers had high blood pressure during pregnancy — either pregnancy-associated hypertension, pre-eclampsia or eclampsia — had more signs of early arterial injury, higher blood pressure, higher body mass index and higher blood sugar than peers.

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A child’s future heart health may be partially shaped before they are born, reports a new Northwestern Medicine study that found pregnancy complications are linked to poorer cardiovascular health in offspring more than 20 years later.

The study found that young adults whose mothers had high blood pressure during pregnancy — either pregnancy-associated hypertension, pre-eclampsia or eclampsia — had more signs of early arterial injury, higher blood pressure, higher body mass index and higher blood sugar than peers.

The authors said the study adds to growing evidence that cardiovascular risk may be transmitted across generations through a combination of biological, environmental and behavioral factors.

“That means we must make sure people maintain good health from childhood into young adulthood, so that if or when someone becomes a parent, they pass on the best opportunity for good health to their children,” said study senior author Dr. Nilay Shah, assistant professor of medicine in the division of cardiology at Northwestern University Feinberg School of Medicine.

How the study was conducted

Shah and colleagues evaluated nearly 1,350 mother-child pairs from the Future of Families and Child Well-Being Study, which enrolled mothers and children at birth between 1998 and 2000 across 20 U.S. cities. The children were then followed into adulthood.

Using delivery hospitalization records, the Northwestern scientists first identified whether mothers experienced pregnancy complications, including high blood pressure during pregnancy, gestational diabetes (high blood sugar during pregnancy) or preterm birth (before 37 weeks of pregnancy).

The three pregnancy complications are on the rise, and affect almost one in four pregnancies in the U.S.

The research team then analyzed cardiovascular health of offspring at age 22, using blood pressure measurements, blood testing, body mass index assessments and carotid artery ultrasounds to look for signs of artery injury.

Finally, the scientists compared participants with and without exposure to each pregnancy complication and adjusted for factors like income, education, difference in birth weight and smoking during pregnancy.

Key findings

At around age 22, participants whose mothers had high blood pressure during pregnancy had:

  • Higher body mass index (+2.8 BMI points)
  • Higher diastolic blood pressure (+2.3 mm Hg)
  • Higher blood sugar levels (+0.2% HbA1c)
  • Thicker artery walls (~0.02 mm)

While the difference in artery wall thickness may seem small, the study authors said it corresponds to roughly three to five years of additional vascular aging. That means arteries looked older and less healthy than expected, which raises the risk of future heart disease.

Other pregnancy complications also showed some long-term effect:

  • Exposure to gestational diabetes was linked to worse blood pressure and some evidence of artery thickening
  • Being born preterm was associated with higher blood sugar levels

‘Most heart disease is preventable’

With pregnancy complications on the rise in the U.S., Shah said the study provides compelling evidence that improving health before and during pregnancy could help reduce heart disease risk in the next generation.

“There is evidence that both parents’ health at the time of conception and during pregnancy influences a child’s health,” he said. “So, promoting health from an early age, like exercising regularly, eating healthfully, never smoking and getting enough sleep, is not just meant for an individual, but doing so may help future generations be healthier, too.”

Shah also emphasizes that risk is not destiny.

“The good news is that most heart disease is preventable,” he said. “If you experienced high blood pressure or high blood sugar during pregnancy, or your child was born early, it does not absolutely mean that your child will have worse health as adults. But I would encourage you to pay attention now to your child’s health behaviors.

“What children learn in childhood sets the stage for their health across their lives. If you are wondering whether your children’s behaviors are healthy, or are considering making a change, please speak with your child’s pediatrician for advice and guidance.”

Other Northwestern co-authors include Emily Lam, Abigail Gauen, Dr. Sadiya Khan, Alexa Freedman and Norrina Allen.

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