Martha Constantine-Paton

Developing Connections

Martha Constantine-Paton studied the formation and modification of synapses – the interconnections between neurons – in order to understand how experience shapes the wiring of the brain. By studying individual neurons in the visual system of developing animals, she showed that a class of molecules known as NMDA receptors plays an essential role in setting the strengths of synapses. NMDA receptors are thought to underlie many aspects of learning throughout life. Constantine-Paton also examined the role these receptors play in developmental disorders that have their origins in early life.

Neuroscientists discover a gene that controls worms’ behavioral state

In a study of worms, MIT neuroscientists have discovered a gene that plays a critical role in controlling the switch between alternative behavioral states, which for humans include hunger and fullness, or sleep and wakefulness.

This gene, which the researchers dubbed vps-50, helps to regulate neuropeptides — tiny proteins that carry messages between neurons or from neurons to other cells. This kind of signaling is important for controlling physiology and behavior in animals, including humans. Deletions of the human counterpart of the vps-50 gene have been found in some people with autism.

“Given what is reported in this paper about how the gene works, coupled with findings by others concerning the genetics of autism, we suggest that the disruption of the function of this gene could promote autism,” says H. Robert Horvitz, the David H. Koch Professor of Biology and a member of MIT’s McGovern Institute for Brain Research.

Horvitz and Martha Constantine-Paton, an MIT professor of brain and cognitive sciences and member of the McGovern Institute, are the senior authors of the study, which appears in the March 3 issue of the journal Current Biology. The paper’s lead authors are former MIT postdocs Nicolas Paquin and Yasunobu Muruta.

Influencing behavior

Neuropeptides, which are involved in brain functions such as reward, metabolism, and learning and memory, are released from cellular structures called dense-core vesicles.

In the new study, the researchers found that the vps-50 gene encodes a protein that is important in the generation of such vesicles and in the release of neuropeptides from them.

They discovered the protein in the worm Caenorhabditis elegans, where it is found primarily in nerve cells. In those cells, vps-50 associates with both synaptic vesicles and dense-core vesicles, which release neurotransmitters such as dopamine and serotonin. The researchers showed that vps-50 is required for maturation of the dense-core vesicles and also regulates activity of a proton pump that acidifies the vesicles. Without the proper acidity level, the vesicles’ ability to produce neuropeptides is impaired.

The researchers also found distinctive behavioral effects in C. elegans worms, which normally change their speed depending on food availability and whether they have recently eaten.

“Worms are the fastest when food (bacteria) is absent, presumably because they are looking for food,” Paquin says. “When they reach food, they slow down, but when you make them hungry for 30 minutes before putting them on food, they slow down even more.”

Worms lacking vps-50 behaved as if they were hungry — moving slowly through a food-rich area even when they were well fed, the researchers found. This suggests that the worms without vps-50 are unable to signal that they are full and continue to behave as if they are hungry. The researchers also found an equivalent gene in mice and showed that it can compensate for loss of the worm version of vps-50, showing that the two genes have the same function.

Human link

One important question raised by the study is how the mouse and human versions of vps-50 affect behavior in those animals, Horvitz says. Although this study focused on switching between hunger and fullness, neuropeptide signaling has been previously shown to control other alternative behaviors such as sleep and wakefulness and also to control social behaviors, such as anxiety.

The researchers suggest that studies of vps-50 might shed light on aspects of autism, because the human version of the gene is missing in some people with autism. Furthermore, a protein known as UNC-31, which is also located in dense-core vesicles has also been linked with autism in humans and mice. When mutated in worms, UNC-31 produces behavioral effects similar to those caused by vps-50 mutations.

“For these reasons, we hope that our studies of vps-50 will provide insights into human neuropsychiatric disorders,” Horvitz says.

The research was funded by the National Institutes of Health and the Simons Center for the Social Brain at MIT.

Martha Constantine-Paton to receive top honors from Tufts University

Martha Constantine-Paton will receive the Dean’s Medal from Tufts University’s School of Arts and Sciences for her “exceptional contributions to the field of developmental neuroscience.” Constantine-Paton, a Tufts alumna, refers to her time at the university as a “turning point” in her life and credits the school for giving her the self-confidence she needed to pursue a career in science. The Dean’s Medal is the highest honor available at each school at Tufts, reserved only “for those select individuals who have made outstanding contributions to the university and to the greater community.”

Constantine-Paton will be awarded the Dean’s Medal on March 25, 2013.

Martha Constantine-Paton wins lifetime achievement award

Constantine-Paton, a leading figure in the field of developmental neuroscience, has been awarded the Society for Neuroscience’s Mika Salpeter Lifetime Achievement Award.

The award recognizes individuals with outstanding career achievements in neuroscience who have also actively promoted the professional advancement of women in neuroscience. Constantine-Paton will be recognized for her achievements during the Society for Neuroscience’s annual meeting this October.

Over the past 30 years, Constantine-Paton has established a reputation as a leading figure in the field of developmental neuroscience. In particular, her pioneering work on NMDA receptor-dependent plasticity laid the groundwork for our current understanding of how the brain becomes correctly wired in response to activity and experience.

She has also mentored many students and postdocs, among them several prominent women scientists, and she is very active in promoting the career development of her junior colleagues.

“Martha’s research contributions have been extremely influential within her field, and her influence has also been felt through her exemplary record of mentoring and service,” says McGovern Institute director Robert Desimone. “Martha’s career indeed represents a lifetime of achievement and I cannot imagine a more deserving recipient for this honor.”