Defects in Brain’s White Matter May Underlie Psychiatric Disease

Neurons have always taken the starring role in research on brain function and disease, but recently members of the brain’s supporting cast, oligodendrocytes, have been getting their due. A study in the lab of Gabriel Corfas, HMS associate professor of neurology and otolaryngology at Children’s Hospital Boston, provides evidence that defects in oligodendrocytes, the cells that make up the brain’s white matter, can cause neural and behavioral changes in mice suggestive of psychiatric disease.

Courtesy Joshua Murtie, PhD, Children’s Hospital Boston

When NRG1–erbB signaling was blocked, oligodendrocytes from the brain’s frontal cortex had a less complex structure than normal, forming fewer branches. Shown are three-dimensional reconstructions of oligodendrocytes from a normal mouse (left) and a mutant mouse (right).

Irregularities have been seen in the white matter of patients with neuropsychiatric diseases like schizophrenia, but it has not been clear whether they are causes or consequences of disease. At the same time, studies have linked genetic changes in the growth factor neuregulin-1 (NRG1) and one of its receptors, erbB4, to schizophrenia and bipolar disorder, but how these changes affect the brain is unknown. Corfas’s team, led by research fellows Kristine Roy and Joshua Murtie, created transgenic mice in which this signaling pathway is blocked in just the brain’s oligodendrocytes.

Examining the brains of the transgenic mice, the team discovered subtle changes in the oligodendrocytes, which send out branches that attach to nerve cell axons, wrapping them in insulating sheaths of myelin. The mice had more oligodendrocytes, but the cells were simpler, with fewer branches and thinner myelin sheaths.

The transgenic mice also behaved differently. When placed in a box, they moved and explored less, and their activity further decreased after repeated exposures. They lingered near the walls, a behavior suggestive of anxiety. Their social interaction was also different; when faced with an intruder mouse, the transgenic mice responded more slowly and took longer to investigate the intruder with repeated exposures. The study, which appeared in the May 8 Proceedings of the National Academy of Sciences, shows that “it’s enough to change white matter in very subtle ways to have a dramatic effect on behavior,” Corfas said.

The transgenic mice also became increasingly hyperactive in response to amphetamine, a sign of defects in the dopamine pathway. The team found a higher level of dopamine receptors and transporters in the neurons of the transgenic mice. The alterations in behavior and dopamine signaling suggest that white matter changes could be a cause rather than a byproduct of neuropsychiatric disease.

Corfas notes that in addition to the genetic alterations known to occur in the neuregulin pathway, environmental insults could also affect it. The next steps, he said, are to clarify how changes in the brain’s white matter could affect how neurons use dopamine and to start looking for evidence in humans of a relationship between neuregulin-1 signaling, white matter defects, and psychiatric disease.

—Courtney Humphries

Magnesium Imbalance in Kidney Disorder Caused by Sodium Channel

The tortuous intestinal tube interfacing the inner and outer worlds is lined with epithelial cells joined by tight junctions. These gasketlike connections form an ion-selective barrier to diffusion between the cells. But not all gaskets are created equal. Their permeability can vary with the cells that contain them, creating biological nuances with implications for a variety of disorders. A recent study, published online April 18 in the Journal of Biological Chemistry by HMS researchers, further characterizes the properties of a junction that is mutated in a genetic disorder of the kidney.

Dating back to the 1950s, physiologists noticed differences in the electrical resistance across epithelia. “It seemed that some gaskets are leakier than others,” said Daniel Goodenough, the Takeda professor of cell biology. Goodenough has studied intercellular junctions since he isolated gap junctions—the connection between one cell’s cytoplasm and another’s—as an HMS graduate student in the 1960s.

A deeper understanding of the functional implications of epithelium-specific leakiness has remained murky. But the rare genetic renal disorder in humans provided some clues. Patients with the disorder, called familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), cannot keep magnesium in their bodies. A 1999 report in Science showed that mutations in the integral membrane protein claudin-16 were responsible for the disorder, and it offered Goodenough and his research team a molecular approach to studying the protein’s role in magnesium homeostasis.

“The first conclusion was that claudin-16 is a selective magnesium channel,” Goodenough said. But preliminary expression data by Jianghui Hou, a research fellow in Goodenough’s lab, demonstrated only broad cation selectivity. As a result, he said, “Our hypothesis was that claudin is actually a sodium channel, not a magnesium channel, and that a loss of sodium permeability results in a failure to generate the driving force for magnesium reabsorption.” They were correct.

Goodenough and Hou used RNA interference to create a claudin-16–deficient mouse. The knockdown of the kidney-specific claudin-16 protein produced a mouse phenotype of the human disorder with high magnesium levels in the urine. Goodenough’s collaborator Markus Bleich, professor of physiology at the University of Kiel in Germany, measured the ion selectivity of the paracellular channels in individual kidney tubules to determine which ions were moving. Mice lacking claudin-16 showed a significant loss of cation selectivity, but were not different in their lithium, sodium, or magnesium permeabilities.

“So, claudin-16 does not simply permit paracellular diffusion of magnesium from the filtrate urine back into the body,” Goodenough said. “It actually functions to generate the electrical driving force for magnesium recovery. Who would have imagined that?”

—Molly McElroy

Stopping Pain Cold During a Root Canal

A simple test commonly used to diagnose the health of a tooth during a checkup may work better than the usual criteria to assess anesthesia and prevent pain during one of the most sensitive of all dental procedures, a root canal, reports Grace Hsiao-Wu and her co-authors at HSDM.

In a randomized, placebo-controlled study of 83 men and women with an average age of 40, those who could not feel a cold stimulus on an anesthetized tooth were about 80 percent less likely to feel pain during a root canal procedure than those whose providers used soft-tissue numbness (such as a lip or tongue with no feeling) as a guide.

“Contrary to popular belief, dentists don’t like to cause people pain,” said Hsiao-Wu, a clinical instructor in restorative dentistry and biomaterials sciences. “It’s important to make sure the tooth is fully anesthetized. If it’s not completely numb, a patient feels it.”

In a root canal procedure, an endodontist makes an opening in the crown of a tooth, removes the inflamed or infected pulp, cleans and shapes the canals, and fills and seals the space. The procedure can save an infected tooth and relieve the severe ache caused by the damaged tissue.

The latest technologies and anesthetics have transformed what was an admittedly painful procedure decades ago to one that is no more uncomfortable than having a filling replaced, according to patient information posted on the website of the American Association of Endodontists. Yet some people may still feel pain at some point during the hour or longer procedure, Hsiao-Wu said.

There is no gold standard to assess the level of anesthetic effect, she explained, but most dentists check soft tissue signs, such as lip and tongue numbness, for lower teeth, which are more difficult to anesthetize fully.

For their study, Hsiao-Wu and her colleagues selected Green Endo-Ice, a precision spray of –26 degrees C (–15 degrees F). Dentists normally use a cold test to aid diagnosis during checkups. The sensation quickly disappears in healthy teeth, but a lingering ache in a particular tooth indicates a potential problem.

In this study, patients but not clinicians were blinded. In the analysis, the researchers controlled for the severity of inflammation and damage, age, gender, tooth location, and amount of local anesthesia.

The common, easy, inexpensive cold test should become the new standard of care preceding endodontic therapy, concluded Hsiao-Wu and her co-authors.
Hsiao-Wu conducted the study during her endodontic residency when she was also earning her MPH from the Harvard School of Public Health. The findings are reported in the April Journal of Endodontics.

—Carol Cruzan Morton

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