Vanderbilt Kennedy Center (VKC) investigator Roger Colbran, Ph.D., Louise B. McGavock Chair and Professor of Molecular Physiology and Biophysics. Dr. Colbran’s research focuses on the role of a single protein, CaMKII, and its impact on brain function in individuals with developmental disabilities.
In the interview below, Colbran shares what inspires his research in developmental disabilities, what he’s learned through his lab’s work, and how membership with the Vanderbilt Kennedy Center helps him achieve his goals.
Tell me about your attraction to developmental disabilities research. Do you have a personal connection to disability?
My family has not been directly impacted by developmental disabilities. However, I have always been struck by the sustained impact of developmental disabilities not only on the affected individuals but also on the lives of their families and loved ones. This provides a large part of my motivation for trying to advance our understanding of the atypical molecular mechanisms that contribute to their development.
What are your current research interests and what problem(s) or challenge(s) does it address?
My lab is focused on understand the molecular processes that involve a single protein, CaMKII, that is critical for normal brain function. Neuronal expression of CaMKII is strongly increased during brain development, becoming very abundant in adult brain regions with well-defined roles in learning and memory. Some of the first studies using mice showed that deletion of CaMKII causes severe deficits in learning and memory, and other behavioral phenotypes associated with disruptions in synaptic communication between neurons.
Although this was first demonstrated over 25 years ago, it has been very challenging to elucidate exactly how neuronal CaMKII regulates synapses and controls complex behaviors. The best efforts of many labs have shown that CaMKII can regulate numerous downstream neuronal processes and functions, but whether and how CaMKII is involved in neurodevelopmental and neuropsychiatric disorders has remained elusive. In particular, given the prominent neuronal roles of CaMKII, it puzzled me that many early genetic studies of neurodevelopmental disorders failed to detect CaMKII mutations. However, a few recent papers have linked several CaMKII mutations to autism and various forms of intellectual disability.
In the coming years, it will be exciting to uncover exactly how these mutations impact normal CaMKII functions, in hopes that this will uncover fundamental molecular processes that can be targeted to develop novel approaches to treat these disorders.
Do you have a story about a research participant or a breakthrough that illustrates the impact of your work?
Nothing would please me more than to be able to say we have made a breakthrough that had a major impact on how we understand and perhaps even treat a major developmental disability. However, that is not really the way that basic science research typically moves forward. Rather, we make advances by thoroughly understanding the current state of knowledge in a particular area and then developing a specific hypothesis or prediction of how something works (or does not work properly in a disease). The best hypotheses are then tested by carefully designing an experiment that provides robust data to either strongly support the prediction, or clearly indicate that we do not understand the problem.
Whether our initial predictions are correct or incorrect, the next step is always to develop a new hypothesis that once again attempts to move overall understanding further forward. My career has perhaps been a little unusual in that I have largely focused on understanding the function and role of one protein for over 30 years (albeit a very important protein!). I have been lucky to work with numerous talented students and postdocs who have invested themselves in rigorously testing the next hypothesis to keep advancing knowledge, to the point where we are beginning to understand how CaMKII mutations can disrupt specific neuronal functions with behavioral consequences.
To me, the impact of our work is most apparent when our papers are cited by other investigators because our findings have been instrumental in guiding their thinking to move work in related areas forward.
What are your reasons for becoming a Vanderbilt Kennedy Center (VKC) Investigator? How does the VKC enhance the work you do?
The diversity of knowledge and numerous approaches adopted by the various members of the VKC community is highly enriching, as reflected in activities at the annual VKC Science Day. This makes it easy for a basic scientist like me to appreciate the real-world broader significance of what we are trying to do and avoid becoming overly bogged down in the molecular minutia of that typically occupies our minds for much of every day. Even more importantly, interactions with other VKC investigators help us identify and develop future research directions that have the greatest potential to achieve our goal of understanding fundamental mechanisms underlying atypical neurodevelopment. This is illustrated by our recent work characterizing the impact of a de novo CaMKII mutation. Another VKC investigator, Jim Sutcliffe, was involved in genetic analyses of families containing individuals diagnosed with autism, and he brought the detection of this mutation to our attention before it was even published. Furthermore, VKC investigators such as Carissa Cascio and Tiffany Woynaroski, with expertise with clinical studies of kids with autism, are helping guide our ongoing behavioral characterization of mice carrying this mutation. Much of our current molecular work is focused on understanding how CaMKII interacts with and regulates other proteins that have been strongly linked to autism and other neurodevelopmental disorders.
Elizabeth Turner is associate director of VKC Communications.