A neurological love connection

November 14, 2021

Few people likely equate neuroscience with a love story. For Robert Carrillo, Assistant Professor of Molecular Genetics and Cell Biology at the University of Chicago and member of the Neuroscience Institute, the romanticized term is an ideal way of explaining his research.

The human brain contains approximately 86 billion neurons, which transmit information to different areas of the brain and between the brain and the rest of the body. To function properly, each neuron must connect with other neurons at specialized junctions known as synapses. However, neurons only form synapses with certain partners. Understanding how and why this process occurs, which is the focus of Carrillo’s work, will ultimately lead to new discoveries about memory formation and retrieval and motor behaviors, both in health and disease.

“It’s like a dating analogy: the neurons encounter a number of potential partners but eventually only one is a perfect match,” Carrillo explained. “The neurons then stabilize and form a synapse, which is the end goal.”

Working with fruit flies, Carrillo and his research team (James Ashley, senior scientist; Meike Lobb-Rabe, Yupu Wang, Renee Zhang, and Rio Salazar, graduate students; Stephanie Dunning, research technician; Luciano Simonetta, PREP scholar; and several University undergraduate students) explore synaptic connectivity in several circuits. In the fly neuromuscular circuit, for example, 33 motor neurons directly control muscle contractions, and the synapses formed between these neurons and their muscle partners resemble synapses in the human brain. Just as in humans, the flies’ neurons do not randomly connect to form synapses: specific neurons must be wired to specific partners to enable proper circuit function. With a circuit map in hand, the Carrillo team went to work to identify the genes and mechanisms that guide the neuron matchmaking process.

Cell surface proteins, molecules that are found on the outside of cells, appear to play key roles in this process. As part of his earlier research, Carrillo and colleagues, including Assistant Professor Engin Özkan in the Department of Biochemistry and Molecular Biology, examined cell surface proteins to determine which bound to one other. Focusing on a subset of fly proteins, the collaborative study found that Dprs (21 proteins) selectively interact with an 11-member subfamily of immunoglobulin superfamily (IgSF) proteins, which they named Dpr-interacting proteins (DIPs). Carrillo’s team went on to reveal that these 32 cell surface proteins are expressed in unique patterns throughout the nervous system, and importantly, Dpr-DIP binding instructs the matching of synaptic partners. In a recent study, they found that interactions between a specific Dpr and DIP are required for motor neurons recognizing their muscle partners. These molecular “matchmakers” also come into play at other pivotal developmental stages, including motor neuron development, and may be essential for several processes that participate in generating a fully functional circuit.

Carrillo is currently looking at the expression of all motor neuron proteins to hopefully learn more about the different coding mechanisms of each neuron.

“Our circuits have a general game plan of how they form connections with one another, but there are variations,” Carrillo said. “If we can figure out how to form new connections, we may eventually be able to overcome connectivity defects found in various neurological diseases.”

After the synapses form and become functional, they are pliable and can respond to alterations by modifying their activity—a process known as synaptic plasticity. This process can have a deep impact on learning and memory and synaptic function during aging. Carrillo’s lab uncovered a unique form of plasticity between neurons that connect to the same target. Using the same circuit that was analyzed for synapse connectivity, Carrillo’s team ablated motor neurons and observed that remaining neurons detect and compensate when a neighboring neuron is no longer functioning appropriately by enlarging in size and elevating its activity. Carrillo plans to continue this research to learn why, if neurons can self-adjust in this way, they are unsuccessful at preventing neurodegenerative diseases that are ultimately result from cell death.

“In our initial research, the neurons were ablated early in development,” Carrillo said. “Is there a specific timeframe during which neurons can still compensate? If neurons in humans can also compensate, is it possible that the genes that drive this synaptic plasticity are also altered in certain diseases? We’re working to find out what these genes are.”

Carrillo and his team are also active in outreach and diversity efforts, including through the Neuroscience Early Stage Scientist Training Program (NESSTP) with Professor Nancy Schwartz (Pediatrics, Biochemistry and Molecular Biology), Professor Peggy Mason (Neurobiology), and Laurie Risner (Kennedy Center Administrator), and at local elementary school science fairs. Next summer, Carrillo will launch two new programs sponsored by a National Science Foundation (NSF) Faculty Early Career Development (CAREER) Program award—one for local high school students and teachers and another for underrepresented undergraduates from Puerto Rico, working closely with Victoria Flores, Associate Director in the Office of the Provost and coordinator of the Leadership Alliance program. UChicago neuroscience faculty interested in serving as mentors for these programs may contact Carrillo directly at robertcarrillo@uchicago.edu

Work in the Carrillo lab is supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke, NSF, the Biological Sciences Division’s Office of Diversity and Inclusion, and the Neuroscience Institute. Learn more about Carrillo’s latest research on his lab website.