Elucidating the Roles of the Ca2+-activated Ion Channels in Essential Tremor

IETF Funded Research

Researcher: Huanghe Yang, M.D., Duke University School of Medicine

Essential tremor (ET) is a complex and progressive neurological disorder that affects more than1% in the general population and 5% in the population over 65 years. After many years’ efforts, we are only beginning to develop some limited understandings on the pathogenesis. Based on extensive animal and human patient studies, we now know that abnormal oscillatory activity of an interconnected brain network, called the cortico-olivo-cerebello-thalamic circuit, is a common feature of ET. The oscillatory activity is controlled by internal clocks, which send out timing signals and orchestrate the cortico-olivo-cerebello-thalamic circuit to work synergistically to control our body movement. The internal clocks in the brain are analogous to the systemic clock in a computer’s mother board, which constantly generates timing signals to precisely coordinate other electrical components to perform various computational tasks. When the clock goes awry, the computer will malfunction. Within the cortico-olivo-cerebello-thalamic circuit, the inferior olivary nucleus is believed to serve as a major internal clock, which generates powerful and rhythmic timing signals to the cerebellum, one of the essential movement control centers in the brain. To further understand the pathophysiology of ET, Dr. Huanghe Yang’s laboratory at Duke University School of Medicine is working on studying how inferior olive neurons convert their rhythmic electrical activities into timing signals and how the rhythmic electrical activities are disrupted during tremor using a combination of mouse models, molecular, cellular, electrophysiological and imaging tools.

Generating and propagating electrical impulses is a basic property of a neuron. This is owing to neurons, as “excitable cells”, possessing various types of proteins called ion channels, which catalyzes inorganic ions, such as calcium, potassium, sodium and chloride, to flux through cell membranes to generate electricity. What’s unique about inferior olivary neurons is that these neurons express a unique set of ion channels that can mutually interact with each other, thereby forming a network where these ion channels sequentially open and close to generate precise and rhythmic electrical impulses. The rhythmicity serves as timing signals to instruct the downstream cerebellar neurons to produce accurate and smooth movement. Discovering a new chloride channel called TMEM16B in inferior olivary neurons recently, Dr. Yang’s team is working on systematically examining how TMEM16B and other ion channels form the ion channel network to control the rhythmicity of inferior olivary neurons. Their study will not only shine new insights on ET pathogenesis and mechanisms, but potentially providing new therapeutics that can be used to alleviate tremor symptoms and lessen functional disability associated with ET.

Conclusion Summary

With the generous support from IETF, we have been making significant progress over the past six months on investigating the roles of the calcium-activated ion channels in ET.