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November 15, 2010

In Research

Researchers surprised by how some brain cells hook up

brain cellImmune cells known as microglia, long thought to be activated in the brain only when fighting infection or injury, are constantly active and likely play a central role in the creation and elimination of synapses.

The finding, reported in the Nov. 2 issue of PloS Biology, catapults the microglia cell from its well-recognized duty of protecting the brain to direct involvement in creating the cellular networks at the core of brain behavior.

Its apparent role as an architect of synapses—junctions between brain cells called neurons—comes as a surprise to researchers long accustomed to thinking of microglia as cells focused exclusively on keeping the brain safe from threats.

brain cells
This image shows dynamic interactions between microglia (yellow) and dendritic spines (green; pointed by white arrowheads during contacts and red arrowheads before or after contacts) over 15 minutes in the living brain.

“When scientists talk about microglia, the talk is almost always about disease. Our work suggests that microglia may actively contribute to learning and memory in the healthy brain, which is something that no one expected,” says Ania Majewska, study leader and an assistant professor of neurobiology and anatomy.

First author Marie-Ève Tremblay, a postdoctoral associate in Majewska’s lab, used two sophisticated imaging techniques to get an unprecedented look at microglia in the brain. She used immunoelectron microscopy and two-photon microscopy to look at how microglia interact with synapses in the brains of healthy mice as their environment changed.

In the experiments, the scientists looked into the brain while the mice were on a normal cycle of light and dark; while the mice were in the dark for several days; and again when the mice went back to a normal light/dark cycle.

The team found a high level of activity among microglia in response to the visual changes that the mice experienced. Even though scientists often say that microglia which are not actively fighting an injury or infection are “at rest,” scientists found that even under normal circumstances, there is no rest for microglia.

Most notably, the scientists found that microglia changed their activity in response to the environment. When the lights were off, microglia contacted more synapses, were more likely to reach toward a particular type of synapse, tended to be larger, and were more likely to appear to be poised to destroy a synapse. When the lights came back on, most of those activities reversed.

The team showed how microglia send out their extensions, which are like tentacles, constantly, oftentimes targeting synapses. The cells also are known to travel remarkably quickly through the very dense and convoluted environment of the brain, traveling perhaps two millionths of a meter in a minute—remarkably fast on a molecular scale.

Tremblay and Majewska showed that microglia touch and wrap around synapses constantly and may have some say in deciding which synapses will survive and which will disappear. Microglia also appear key to creating or changing the extracellular space around synapses, a factor that would profoundly affect synapse function. The team even found indications that microglia may be involved in destroying synapses through a process known as phagocytosis. Microglia had extensive interactions with tiny lollipop-shaped structures called dendritic spines, which are essential for a neuron’s ability to connect with other nerve cells that transmit excitatory signals. Eliminating dendritic spines is one way to destroy synapses.

The findings are timely for scientists who are increasingly studying links between the nervous and immune systems, Tremblay says. The role of microglial cells themselves is being looked at in an array of conditions, including Parkinson’s and Alzheimer’s diseases, schizophrenia, obsessive-compulsive disorder, and autism.

The work was funded by the National Eye Institute, the Whitehall Foundation, the Alfred P. Sloan Foundation, and a Career Award from the Burroughs Wellcome Fund.

Hypertension in kids linked to learning disabilities

Children who have hypertension are much more likely to have learning disabilities than children with normal blood pressure, according to a new Medical Center study published in the journal, Pediatrics. In fact, when variables such as socio-economic levels are evened out, children with hypertension were four times more likely to have cognitive problems.

“This study also found that children with hypertension are more likely to have ADHD (attention deficit hyperactivity disorder),” says Heather Adams, an assistant professor of neurology and pediatrics and an author of the study. “Although retrospective, this work adds to the growing evidence of an association between hypertension and cognitive function.”

Among the study’s 201 patients, all of whom had been referred to a pediatric hypertension clinic at Golisano Children’s Hospital, 101 actually had hypertension, or sustained high blood pressure, determined by 24-hour ambulatory monitoring or monitoring by a school nurse or at home. Overall, 18 percent of the children had learning disabilities, well above the general population’s rate of 5 percent. But the percentage among those without hypertension was closer to 9 percent, and among those with hypertension, the rate jumped to 28 percent. All of the children were between 10 and 18 years old, and parents reported the children’s learning disability and ADHD diagnoses.

This study is part of a series of hypertension studies by Golisano Children’s Hospital researchers, led by principal investigator Marc Lande, a pediatric nephrologist, but it was the first that included children with ADHD. Previous studies excluded them because ADHD medications can increase blood pressure. Researchers included them this time because, although it is possible that some of the children’s hypertension was caused by medications, it is also possible that the higher rate of ADHD among children with hypertension is a reflection of neurocognitive problems caused by hypertension. Twenty percent of the children with hypertension had ADHD whereas only 7 percent of those without hypertension had ADHD among the study participants. And even when ADHD was factored out of the analyses, there was still a higher rate of learning disabilities in the hypertensive, compared to the nonhypertensive group of children.

The study was funded by a grant from the National Institutes of Health. The authors have no conflicts to disclose.


Low vitamin D may raise cancer risk

Two new vitamin D studies from the Medical Center suggest ties between a deficiency of D and breast and colon cancer, particularly among African Americans.

The research adds to mounting evidence that some connection exists between vitamin D and cancer, although it is not yet known how vitamin D modifies or contributes to cancer risk.

In retrospective study of 224 women being treated for breast cancer at the Wilmot Cancer Center, researchers found that 66 percent were either severely deficient or moderately deficient of vitamin D.

The deficiency was particularly high among non-caucasians and women with later-stage disease, says Alissa Huston, an assistant professor of medicine.

African American women had the lowest mean levels of vitamin D, as compared to white or Hispanic patients, although the study population was small. Black women can be prone to more aggressive breast cancer, but it is not known whether vitamin D plays a role in this, Huston said, adding that further study is needed.

“Our data certainly suggests that it is important to test patients for serum vitamin D levels and, if necessary, treat the deficiency along with the disease,” says Huston, a specialist in Wilmot’s Comprehensive Breast Cancer Program. “In some cases, weekly high doses of vitamin D are needed to bring the patient up to sufficient levels.”

In a separate study reported online in Cancer, investigators, led by Kevin Fiscella, a professor of family medicine, of community and preventive medicine, and of oncology, found that vitamin D deficiency among African Americans may explain a persistent mystery in colorectal cancer: why black people die of this disease far more often than whites.

Fiscella constructed an epidemiology study of American adults, using a publicly available health data. Among 91 deaths from colorectal cancer during the study period, researchers assessed a range of factors that could contribute to death, from age and race, to smoking status and weight, to history of colorectal cancer and access to medical care through health insurance.

Researchers found that being African American doubled the risk of dying from colorectal cancer. Furthermore, vitamin D deficiency based on a blood test explained about 40 percent of the risk associated with being African American.