Rebecca Seal, PhD

The most pervasive neurotransmitter in the nervous system – glutamate – activates or excites neurons and is essential for neural communication, learning, and memory. There are three transporter proteins known as the vesicular glutamate transporters (VGLUTs 1-3) that are responsible for packaging the excitatory neurotransmitter into synaptic vesicles for regulated neurotransmission. Using a mouse model, Rebecca Seal, an associate professor of neurobiology at the University of Pittsburgh, is helping to understand the role of one transporter, VGLUT3, in the evolution of neural circuits that regulate pain, hearing, and Parkinson’s disease. Seal’s work, which is based on studies of this receptor system, is helping to define the relationship between neurological circuits and neurological disorders. Her studies should contribute to a better understanding of, and treatments for, a range of neurodegenerative conditions.

In earlier work, Seal found that knocking out (KO) the gene for VGLUT3 in mice resulted in profound deafness (Seal et al Neuron 2008).  Her team determined that a transporter is responsible for packaging glutamate into synaptic vesicles of inner hair cells (IHCs), the primary sensory cells of the auditory system, which convert sound waves into electrochemical signals that are decoded by the nervous system to generate perceptions of sound.  Without VGLUT3, IHCs cannot transfer sound information to the rest of the auditory circuit.  Using this mouse model (a VGLUT3 KO mouse), Seal demonstrated for the first time that viral gene therapy applied to the cochlea can rescue profound deafness (Akil et al Neuron 2012), a finding that could benefit families affected by inherited deafness.

Seal also found that mice lacking VGLUT3 do not develop mechanical hypersensitivity after injury and show reduced acute mechanical pain (Seal et al Nature, 2009). All other types of pain and skin sensation are normal in these mice. Further investigation by the Seal lab at the University of Pittsburgh showed that VGLUT3 has a critical role in setting up the pain circuit found in part of the spinal cord (dorsal horn) during early postnatal development (Peirs et al Neuron, 2015).  Importantly, she also demonstrated that the dorsal horn neurons that express VGLUT3 are required to transmit pain in the adult. She is now expanding this work to the rest of the neural circuit for mechanical hypersensitivity.  Her long-term goal is to identify the key elements that make up neural circuits underlying persistent pain (mechanical and thermal) induced by different types of injuries (single and multiple nerve injuries or inflammatory injury).  Persistent pain is a major clinical problem with over 100 million sufferers in the United States.  Current treatments often lack efficacy or have serious side effects such as addiction.  Thus, there is a strong need for new pain therapies.  Identifying the neural circuits that underlie persistent pain will generate a more comprehensive understanding of pain mechanisms, which will then open the door to the development of many new strategies for the treatment of pain.

Seal developed a solid scientific reputation through her work on VGLUT3 in hearing loss and in pain, beginning when she was a postdoctoral fellow in the Vollum Institute at Oregon Health and Sciences University (OHSU). She received her doctorate from OHSU after receiving her bachelor’s degree from the University of Oregon. She came to the University of Pittsburgh in the fall of 2010 after completing a post-doc at the University of California, San Francisco. Her laboratory at Pitt, which uses a number of cutting-edge genetic tools, is making substantial progress in understanding the neural circuitry underlying neurological disorders such as Parkinson’s disease and chronic pain.

A member of the Society for Neuroscience, Seal received a prestigious NIH predoctoral fellowship, as well as several NIH post-doctoral training awards and a NARSAD (now the Brain and Behavior Research Foundation) Young Investigator Award. She is a Rita Allen Scholar and a recipient of an Innovation Award from the American Diabetes Association.

Making a discovery that could benefit diseases like Parkinson’s Disease

When she created a VGLUT3 KO mouse, Seal was surprised to find that mice were hypermobile during their waking hours. Knowing that another neurotransmitter, dopamine, is important for movement, she wondered whether increases in this neurotransmitter were causing the hypermobility in the VGLUT3 KO mice.  Experiments showed that this was indeed the case; dopamine levels were increased during the waking hours. Since loss of dopamine is a characteristic feature of Parkinson’s disease and dopamine replacement therapy is the gold standard treatment, the increase in dopamine during waking hours suggested that the mice might show regular motor behavior while awake in a Parkinson’s disease model (where dopamine is artificially depleted).

Thinking she would induce Parkinsonian symptoms (reduced movement), Seal depleted dopamine production within the brain of VGLUT3 KO mice and found, unexpectedly, that mice moved normally both during waking and sleeping hours, a time when mice are typically less mobile. Despite an experimental reduction in dopamine production, the mice behaved as if nothing was wrong. How could this be? The absence of the VGLUT3 transporter somehow stimulated specific neurons to have more spines within a part of the brain called the striatum. Seal hypothesizes that these spines play an important role in the circuitry underlying the preserved movement in dopamine-depleted VGLUT3 KO mice. Ultimately, understanding how VGLUT3 changes midbrain dopamine output could lead to new ways to manipulate brain functions influenced by dopamine. This work is providing a rare and exciting opportunity to gain insight into how striatal dopamine signaling and plasticity affect movement both in health and in Parkinson’s disease. The work also opens new avenues for therapeutic intervention in PD.

Striatal neurons expressing spines that are important in dopamine signaling in PD.