April 2016

Tracing Neurons’ Migration Suggests Cause of Brain Development Defects

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By following the journey of how newly born neurons migrate in the developing cerebral cortex, the part of our brain responsible for conscious thought and higher order functioning, a study team at The Children’s Hospital of Philadelphia provided new insights into how disruptions in this pathway during early brain formation may lead to neurodevelopmental defects.

Drawing on both neuroscience and developmental biology, the researchers described in the journal Cell Reports how two types of neurons — projection neurons and interneurons — take different routes to reach their destination during fetal brain development. Based on previous research, the study team reasoned that projection neurons require less energy to migrate radially than interneurons that migrate tangentially. In other words, projection neurons take the fast lane along the highway, and interneurons explore a circuitous, scenic route.

Both types of neurons have travel companions — small organelles within the cell called mitochondria — that provide the energy for their locomotion along these trips. The research team’s new work suggests that mitochondrial dysfunction could interfere with the interneurons’ progress to get from their birthplace to their station in the brain.

The study’s first author, Erika Lin-Hendel, a graduate student in the School of Veterinary Medicine at the University of Pennsylvania, consulted with CHOP experts, including Douglas Wallace, PhD, director of CHOP’s Center for Mitochondrial and Epigenomic Medicine, to figure out how to produce live images of moving mitochondria inside moving neuron cells. The movies she created showed that mitochondria shift quite actively in the tangentially migrating interneurons. Meanwhile, mitochondria appear to sit in front of the nucleus in radially migrating projection neurons without exerting as much effort.

“When a neuron migrates, its fundamental challenge is how to move its nucleus, which has very tightly packed DNA and is heavy,” explained Stewart Anderson, MD, of CHOP’s department of Psychiatry who is co-senior author of the paper and Lin-Hendel’s mentor. “Essentially it is a sack of potatoes that the neuron cell is trying to move. When projection neurons migrate radially, they grab and pull the sack behind them. They don’t need a lot of energy to do their migration. But the tangentially migrating interneurons don’t have anything to grab onto. They reach and then squeeze the cell behind the nucleus to push it forward, kind of like sliding a golf ball through a garden hose. The interneurons need a lot of energy to do this, so a bioenergetics problem could hinder their ability to get placed in the right location in the cerebral cortex.”

Once the study team saw clearly that the mitochondria localized differently in the interneurons, the next step was to demonstrate that their energetic requirements also differed. In order to accomplish this, the researchers studied mice with a mutation in a gene that encodes for a protein that is necessary to move adenosine triphosphate (ATP) outside of the mitochondria. ATP is like charged batteries that are synthesized by the tiny energy factories. In these mice, the researchers observed that since ATP could not get out of the mitochondria, the interneuron cells did not have enough oomph, and their migration slowed down and became disoriented. Yet, the projection neurons’ migration seemed to be unaffected.

They demonstrated this same concept in another way by studying migrating neurons in a petri dish and treating them with a poison that halted mitochondrial ability to transport ATP. At a very low concentration, the poison blocked interneurons’ tangential migration but did not block the projection neurons’ radial migration.

“These results provide a new way of thinking about how metabolic challenges selectively can affect populations of cells,” said Dr. Anderson, who also is an associate professor of Psychiatry in the Perelman School of Medicine at the University of Pennsylvania.

The bulk of the processes of neuronal migration occur between 10 and 30 weeks gestation. A pregnancy complication or some type of chronic oxidative stress, such as from maternal smoking, drug use, or placental dysfunction, that reduces the fetus’ mitochondrial energy production could leave the interneurons stranded. This may partly explain why many patients with mitochondrial disease, which affects about one in 5,000 people, experience neurological symptoms, like seizures, that are suggestive of a failed function by the inhibitory interneurons.

Projection neurons, which excite their targets, and interneurons, which use inhibition to balance and to shape the flow of the excitation, must work in concert. Otherwise, hypersynchronous discharge of a population of cortical projection neurons can cause conditions such as childhood epilepsy. Or, if there is not enough synchrony, then the system becomes noisy, with inadequate brain rhythms, possibly causing intellectual disability and autism spectrum disorder. An infant who has inadequate numbers of interneurons because they never arrived at the place where they are supposed to be during the brain’s formative period may not be able to achieve or maintain this delicate state of equilibrium.

“The implications of these findings are that some of the solutions may be even harder to achieve than we had previously appreciated,” Dr. Anderson said. “The idea that the problem might be altered placement versus altered function of the interneurons shifts our thinking.”

The researchers’ novel observations could help to guide new approaches to identify fetal complications earlier, reduce oxidative stress, and support placental health to help ensure that interneurons have enough energy to stay on the right course. Other future strategies that Dr. Anderson’s laboratory is at an early stage of exploring are interneuron cell replacement therapies.

The study team also included co-senior author Jeffrey Golden, MD, formerly of CHOP and currently chair of the department of Pathology at Brigham and Women’s Hospital, Harvard Medical School; and Meagan McManus, PhD, of CHOP’s Center for Mitochondrial and Epigenomic Medicine and the department of Pathology and Laboratory Medicine at Penn.

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