Just as every country is protected by a tightly sealed border, so too is the brain. Breaches in the brain’s border wall cause many neurological dysfunctions, but a leaky brain border can also cause neuropsychiatric disorders, according to a new study from researchers at the University of Pennsylvania.

The brain’s border wall, called the blood-brain barrier, is a tightly sealed barricade that separates fluid bathing brain tissue from substances circulating in the bloodstream. This cellular cerebral seal is essential, because the brain operates on a knife edge. Even a slight change in composition of fluid bathing the brain can disrupt its function.

A glass of wine or a cup of coffee will tip brain function in either direction. Imagine the consequences if blood cells or neurotoxic substances in blood penetrate the blood-brain border. The effects can be disastrous. While this is well understood by neurologists, the possibility that psychological illnesses, such as autism spectrum disorders and schizophrenia, could be caused by a leaky blood-brain barrier has not been fully appreciated.

The new study, on the rare inherited disorder DiGeorge syndrome, reveals that a leaky blood-brain barrier can cause autism spectrum-like symptoms and that a drug that repairs the defect in the border wall relieves the psychological impairments. DiGeorge syndrome, caused by a missing stretch of chromosome 22, can have wide ranging effects on the brain and body, but affected patients also have a 25-fold increased risk of developing psychosis, and one in four individuals with the syndrome develops schizophrenia.

Previous research had found that the blood-brain barrier is leaky in this genetic disorder, raising the question in the researchers’ minds of whether that defect could be causing the psychiatric symptoms. To understand how this might be possible, and how the scientists set about testing their hypothesis, we need to take a closer look at the blood-brain barrier.

The Brain’s Border Wall

The blood-brain barrier is formed by specialized cells that are stuck tightly to each other by molecules on their surface (cell adhesion molecules) that act like caulk. The cells are so tightly stuck to each other that fluid that normally surrounds all cells in the body is excluded from flowing between them. This layer of tightly adhered cells forms an impenetrable cellular wall that lines blood capillaries in the brain.

The import and export of vital substances across the cellular shield are essential for brain function. Cross-border transport of substances is highly regulated by these cells. Analysis of chromosome 22 in DiGeorge syndrome, revealed that six of the missing genes make proteins that are in mitochondria. This is intriguing because the blood-brain barrier cells are packed with mitochondria.

Mitochondria are the sausage-shaped cellular organelles that generate the energy source ATP (adenosine triphosphate) fueling all cellular function. Abundance of the organelles in cells that form the blood-brain-barrier might be needed for production of the energy required to maintain the border and to transport materials across it.

This raises several questions: Are mitochondria impaired in blood-brain border cells in DiGeorge syndrome? If so, does this cause a leaky blood-brain barrier? If both questions turn out to be true, is social behavior affected?

Mitochondria Implicated in Leaky Blood-Brain Barrier in DiGeorge Syndrome

Using cells taken from DiGeorge syndrome patients and reprogrammed into an embryonic state that researchers can use to produce specific kinds of adult cells (so called induced pluripotent stem cells [iPSCs]), the researchers grew in culture the microvascular endothelial cells that lack the stretch of chromosome 22 genes. They compared these cells with normal blood-brain barrier cells.

Tests showed that the DiGeorge syndrome cells produced less ATP. When they examined these cells under an electron microscope from the brains of mice that had this stretch of chromosome 22 removed, they saw that the mitochondria were pale compared to normal mitochondria. Further tests performed on the iPSC cells from human DiGeorge patients grown in culture showed that the cells formed a leakier barrier.

The findings implicate impaired mitochondria in blood-brain barrier cells as the culprits weakening the barrier in DiGeorge syndrome. But does this cause behavioral difficulties in social interaction? To test this, the researchers measured how much time mice spent interacting with a novel mouse versus one they had already encountered. The mice with the part of chromosome 22 that is missing in DiGeorge patients performed poorly on the test compared with normal mice. Normally mice will spend more time interacting with a new mouse, but the DiGeorge syndrome mice did not show such normal behavior.

So far in this investigation, the evidence supports the hypothesis that defective mitochondria causing a leaky blood-brain barrier are responsible for the behavioral effects in social interaction, but all of this evidence is circumstantial—just correlations. A definitive test would be to restore normal mitochondrial function in the Di George syndrome mice and see whether their behavior in the social interaction test improved.

When the researchers applied a drug known to increase ATP production in mitochondria (bezafibrate), they found that the barrier formed by the mutant microvascular endothelial cells in culture was strengthened. Also, the pale mitochondria in DiGeorge syndrome mice regained their normal appearance, and the deficiency in the social interaction test was eliminated.

This research may lead to new treatments for people with DiGeorge syndrome. But the finding that a leaky blood-brain barrier can affect behavior in tests of social interaction, suggests that other psychiatric conditions could also arise from defects in the cellular border separating blood and brain.