- B.A., Biology, Carleton College, Northfield, MN (1990)
- Ph.D., Neuroscience, Washington University School of Medicine, St. Louis, MO (1996)
- Stanford University, Howard Hughes Medical Institute
My main career goals focus on understanding how the rich physiologic diversity of ion currents regulates the excitability of neurons and circuits. During the first part of my career, my interests lay primarily in characterizing the molecular diversity of ion channels. The goals of this work were to understand what the molecular toolset of neuronal signaling contained and how it evolved. I began by studying the evolution of voltage-gated K+ channels in Dr. Larry Salkoff’s lab and continued in Dr. Richard Aldrich’s lab working on large-conductance calcium-activated (BK) channels. I then moved to private industry to identify and characterize the complete mammalian ion channel complement during the beginning of the genome sequencing era. While most of my early work in industry focused on identification of novel ion channels with drug target potential, I maintained a strong interest in understanding the evolutionary history of the animal ion channel set because evolutionary conservation is such a powerful indicator for fundamentally important proteins. We now know that there are 45 types of ion channel that have been conserved throughout the evolution of animal species; these represent a non-redundant set of ion channels required for animal physiology. My interests now lie in understanding how these fundamental classes of ion channels uniquely contribute to the function of the nervous system; I have returned to the academic world to pursue these interests. The lab is currently focused on understanding how K+ channels control firing threshold in neurons, and maintains a strong interest in the role of ion channels in the generation of sensory potentials.
K+ channels and control of firing threshold
We are interested in how ion channels control the excitability of neurons and how this influences the activity of neural circuits. Abnormal hyperexcitability is a defining feature of clinically significant diseases such as epilepsy. Our understanding of these diseases currently is limited by gaps in our understanding of how neuronal excitability is controlled. Voltage-gated K+ currents that activate below the threshold for action potential initiation can have a profound influence on excitability, but the molecular basis and modulation of these currents is still not well understood. We have undertaken a major effort to dissect the physiological roles of these currents using both genetic and pharmacologic approaches. We recently have found that the K+ channel Kv12.2 accounts for a significant fraction of sub-threshold K+ current in hippocampal neurons. Kv12.2 has a strong influence on firing threshold and loss of the Kv12.2 current leads to epilepsy. We currently are investigating Kv12.2 as a potential new therapeutic target for seizure control. We are expanding our work to examine the roles of Kv12 channels in sensory perception and to identify other key components of sub-threshold K+ currents in central neurons.
We are using genetic manipulations of K+ channels to gain new insights into how hyperexcitability in individual neurons leads to epileptogenesis. How is homeostatic control of circuit excitability lost? What pathways are engaged to compensate for neuronal hyperexcitability? To answer these questions, our goal is to develop a system to track excitability phenotype at the level of individual neurons.
Evolution of the Nervous System
The nervous system first evolved in the last common ancestors of Cnidarians and Bilaterians. Cnidarian nervous systems are anatomically dispersed and far simpler than those of Bilaterians, yet the diversity of neuronal signaling proteins rivals our own. We have an interest in understanding how Cnidarians use this diverse palette of neuronal signaling proteins to generate complex behaviors from a simple nervous system.
We have a strong interest in understanding how ion channels generate sensory potentials. Past work has focused on defining the role of TRP channels in temperature sensation. More recently we have become interested in understanding how information on illumination is fed to the circadian clock. We have used in vitro and genetic approaches to show that melanopsin is the photosensor of a special class of intrinsically photosensitive retinal ganglion cells that entrain the clock neurons of the suprachiasmatic nucleus. We currently are investigating the mechanistic basis of light-dependent changes in clock neuron excitability.
Zhang X., F. Bertaso, J. Yoo, K. Baumgartel, S. M. Clancy, V. Lee, C. Cienfuegos, C. Wilmot, J. Avis, T. Huynh, C. Daguia, C. Schmedt, J. Noebels, and T. Jegla. 2010. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neuroscience 13: 1056-1058.
Clancy, S. M., B. Chen, F. Bertaso, J. Mamet, and T. Jegla. 2009. KCNE1 and KCNE3 beta-subunits regulate membrane surface expression of Kv12.2 K(+) channels in vitro and form a tripartite complex in vivo. PLoS ONE 4(7): e6330.
Zhang, X., B. Bursulaya, C. Lee, B. Chen, K. Pivaroff, and T. Jegla. 2009. Divalent cations slow activation of EAG family K+ channels through direct binding to S4. Biophysical Journal 97(1): 110-20.
Jegla, T., C. Zmasek, S. Batalov, and S., K. Nayak. 2009. Evolution of the human ion channel set. Comb. Chem. High Throughput Screen. 2009 12(1): 2-23.
Xiao, B., A. E. Dubin, B. Bursulaya, V. Viswanath, T. J. Jegla, and A. Patapoutian. 2008. Identification of transmembrane domain 5 as a critical molecular determinant of menthol sensitivity in mammalian TRPA1 channels. J. Neurosci. 28(39): 9640-51.
Hamada, F. N., M. Rosenzweig, K. Kang, S. R. Pulver, A. Ghezzi, T. J. Jegla, and P. A. Garrity. 2008. An internal thermal sensor controlling temperature preference in Drosophila. Nature 454(7201): 217-20.
Hatori, M., H. Le, C. Vollmers, S. R. Keding, N. Tanaka, C. Schmedt, T. Jegla, and S. Panda. 2008. Inducible ablation of melanopsin-expressing retinal ganglion cells reveals their central role in non-image forming visual responses. PLoS ONE 3(6): e2451.
Petrus, M., A. M. Peier, M. Bandell, S. W. Hwang, T. Huynh, N. Olney, T. Jegla, and A. Patapoutian. 2007. A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition. Mol. Pain. 3:40.
Nayak, S., T. Jegla, and S. Panda. 2007. Role of a novel photopigment, melanopsin, in behavioral adaptation to light. Cell. Mol. Life Sci. 64(2): 144-54.
Panda, S., S. Nayak, B. Campo, J. Hogenesch, and T. Jegla. 2005. Illumination of the melanopsin signaling pathway. Science 307(5709): 600-604.