Elly Nedivi

With chances to collaborate all around her on campus, the professor of brain and cognitive sciences feels like she always has an advantage in developing tools that enable venturing into new territory and finding unexpected discoveries. One hope is to understand disease better, like the above-mentioned bipolar disorder. In her research, she’s looking to develop a genetic test that could end the all-too-common misdiagnoses, the years of frustration, and instead advance life-changing treatments. That all hinges on the focus on her lab’s work, which is understanding the ability of the nervous system to change, adapt, and reorganize its structure and functions when faced with any kind of new experience.

“If we know more about that, the brain’s plasticity, we know what the points are where we can intervene to help,” she says.

The Better Ability to See
It’s a basic, almost obvious, part of most research. If you want to study something, you have to be able to see it, and the more you can see, the more you can potentially learn. Nedivi says that her edge in this regard is her longtime collaboration with colleague Peter So, professor of mechanical and biomedical engineering. Together, they’ve custom-built high-resolution microscopes and developed the biotechnology to label specific proteins in different colors in living animals.

In her lab, it’s allowed Nedivi to highlight both sides of synapses, the connections between neurons that send signals, and where plasticity manifests. She’s also been able to use the multicolor microscopy system to distinguish inhibitory synapses from excitatory ones, something that hadn’t been done. This ongoing collaboration and the power of these microscopes have resulted in a continually expanding understanding of plasticity, as it happens in the living brain.

“We all get the first look,” she says. “We keep finding new things, some of which we weren’t really looking for or weren’t expecting,” she says.

One discovery has been that with the different types of neurons in the brain, “not all connections are created equally.” Some are more dynamic; some are more rigid. That connections are inhibitory and excitatory isn’t new, but what Nedivi found is that inhibitory ones are more flexible, i.e., more plastic. Since inhibitory neurons are only 15 percent of the brain, it was easy to overlook them and believe that they’re not doing important things. But, she says, in actuality, “they are where all the action is happening in terms of circuit flexibility and changing connectivity.”

Another prevailing attitude was that the difference between inhibitory and excitatory was merely valance; one is positive, one negative. But what Nedivi has learned is that inhibitory neurons change connections often, but rather than changing location, “they flicker in and out.” It’s a real-time way that they modulate the activity of the excitatory network in animals as their brains adapt to experience.

Without the equipment, old approaches and attitudes would linger. But now, she can discover what wasn’t even imaginable. “They force you to rethink how everything works,” Nedivi says. And the greater insight means smarter therapies. “Your ability to intervene depends on your knowing what parts of the circuit are amenable to change, and that’s where you’re more likely to be able to make a difference.”

Changing the Course of Bipolar Disorder
She’s also been able to more clearly see the effects of mutations on certain genes involved in plasticity. One specifically, SYNE1, is tied with bipolar disorder, a condition that has a genetic overlap with schizophrenia and depression. SYNE1 encodes a brain-specific protein, CPG2, which Nedivi has shown plays a critical role in regulating the neurotransmitter glutamate in synapses. She’s been able to see that people with bipolar disorder have a low-level amount of CPG2, and Nedivi has tied that reduction to specific mutations in SYNE1. In lab animals, she has shown how some mutations affect neurons, potentially contributing to the pathology of bipolar disorder.

That finding gives her hope in creating a diagnostic test. As it stands, there is currently no available biomarker for bipolar disorder. Diagnosis can sometimes take up 15 years, Nedivi says. It involves observation, waiting, and subjective evaluation. A patient cycles between depression and mania, and since the depression is more frequent, that can become the focus, resulting in a misdiagnosis of depression, and the wrong medication is prescribed. It’s all exacerbated when it’s a child, and doctors want to wait for “classic symptoms” to appear.

But that’s a long wait for a not insignificant group of people. Bipolar disorder affects 1-2 percent of the population. “It’s the most genetically penetrant of all the neuropsychiatric disorders,” she says. If a genetic test existed, depression could be ruled out. Family history could be established. The appropriate treatment could be sought. Most importantly, years of suffering could be eliminated.

“Having a biomarker that you could diagnose, that is not subjective, would be a huge tool in this area, and a first in the category of neuropsychiatric disorders,” Nedivi says. “And the population size that could benefit is orders of magnitude higher than any genetic diagnostic test that exists today.”

Getting Records in Order
As much as Nedivi studies the brain in her lab, she also studies patient genetic records. Like microscopes, they offer data and a greater depth and understanding of plasticity, brain disorders, and the possible treatments. Again, Nedivi is in an enviable position, being in Cambridge at MIT, right across the river from Boston and all its hospitals.

But there’s a stumbling block. Medical records aren’t always modernized or well-organized. It can make it difficult to find case studies. Bipolar patients have long and complex medical histories, which means that to select patient groups for analysis, someone has to physically read through the files and pull out the appropriate matches.

Nedivi would love to find a way to make it work because untapped potential exists in connecting a mutation with a known cellular consequence and a patient’s clinical history.

“I think the potential is huge, both in terms of commercial applications,” she says, “but just also huge in terms of the impact on people’s lives.”