427A Burrill Hall
407 South Goodwin Avenue
Urbana, IL 61801
Disease Research Interests
Neurological and Behavioral Disorders
Mechanisms underlying Homeostatic Plasticity and Epilepsy
Epilepsy is a common chronic brain disorder that is caused by excessive brain activity clinically characterized as seizures. About 40% of epilepsy is associated with genetic mutations. The cause for the rest of epilepsy is unclear. Since ion channels are critical regulators of neuronal activity, the goals of my research program at the University of Illinois at Urbana Champaign (UIUC) have been to (1) understand how epilepsy mutations affect ion channel function and lead to hyperexcitability in inherited or de novo epilepsy, and (2) identify molecular mechanisms that alter ion channels to cause hyperexcitability in acquired epilepsy.
To investigate these two areas, my lab uses interdisciplinary approaches including primary neuronal culture, live and fixed microscopy, biochemistry, electrophysiology, and mouse genetics.
(1) What are the mechanisms underlying polarized localization of KCNQ channels?
My lab has a keen interest in specific neuronal location of ion channels and their roles in intrinsic excitability and epilepsy. We study KCNQ/Kv7 potassium channels that prevent repetitive and burst firing of action potentials, and are mutated in humans who have benign familial neonatal epilepsy (BFNE), severe symptomatic drug-resistant epileptic encephalopathy, intellectual disability, and autism.
We are actively investigating how mutations of Kv7 channels associated with BFNE and epileptic encephalopathy disrupt their functions and neuronal distribution, ultimately leading to neuronal hyperexcitability and epilepsy. Since the fundamental function of a neuron depends critically on precise localization and density of these channels, we also study the mechanisms by which polarized distribution of Kv7 channels in axons is established, maintained, and regulated. My laboratory has made significant contributions to the mechanistic understanding of epilepsy mutations and axonal targeting of Kv7 channels (Cavaretta et al., 2014; Kim et al., submitted; Zhang et al, in preparation).
Understanding these fundamental physiologic and pathologic mechanisms involving Kv7 channel trafficking will help us develop therapeutic strategy to reverse the effects of epilepsy mutations.
(2) What are the molecular mechanisms underlying homeostatic plasticity?
To identify mechanisms underlying plasticity of intrinsic membrane properties, we focus on homeostatic plasticity, which is an ability of neurons to adapt their electrical activity within a physiologic range in response to neuronal activity or sensory experience. The fundamental question is: “when and how do neurons exploit homeostatic plasticity to stabilize their network as a normal adaptive response, or to cause persistent hyperexcitability as a pathological manifestation in epilepsy?” To answer this, we must first understand how homeostatic plasticity is induced in the normal brain. When I started my own laboratory, no molecular players and signaling pathways were identified for homeostatic plasticity of intrinsic excitability.
My laboratory has identified the signaling pathways underlying homeostatic control of intrinsic excitability in cultured hippocampal neurons, which are distinct from homeostatic synaptic scaling (Lee and Chung, 2014; Lee et al., 2015). Using unbiased gene expression profiling, we have identified genes that are regulated during induction of homeostatic plasticity. They encode multiple regulators of excitability (such as potassium channels) and synaptic transmission (such as STEP61). Our follow-up studies discovered that reduced Kv7 current and Kv7.3 level are associated with homeostatic scaling of hippocampal excitability (Lee et al., 2015), whereas striatal-enriched protein tyrosine phosphatase (STEP61) mediates homeostatic plasticity of excitatory synaptic strength by modulating tyrosine phosphorylation of AMPA and NMDA receptors (Jang et al., 2015; Jang et al., 2016). We also identified that prolonged seizures are associated with caspase-dependent cleavage and down-regulation of GIRK potassium channels (Baculis et al., 2017).
Current research interests in plasticity include (1) the function and regulation of axonal Kv7 channels in homeostatic plasticity of hippocampal circuits, and (2) the role of STEP61 in homeostatic plasticity during pathogenesis of epilepsy and Alzheimer's disease, and (3) development of novel transgenic mice to study homeostatic plasticity in vivo.
B.S. 1995 Cornell University, Ithaca, NY
Ph.D. 2002 Johns Hopkins University School of Medicine, Baltimore, MD
Postdoc 2002-2009 University of California, San Francisco, CA
Awards and Honors
Cornell University-HHMI Undergraduate Research Fellowship (1994)
Paul Ehrlich Young Investigator Award, Johns Hopkins University (2002)
Ruth L. Kirschstein National Research Service Award (2004-2007)
Basil O'Connor Starter Scholar Research Award, March of Dimes Foundation (2011-2013)
Carver Young Investigator Competition Award, Roy J. Carver Charitable Trust (2011-2014)
Targeted Research Initiative for Severe Symptomatic Epilepsies Grant Award, Epilepsy Foundation (2013-2014)
James E. Heath Award for excellence in teaching in Physiology, University of Illinois (2014)
Additional Campus Affiliations
Associate Professor, Molecular and Integrative Physiology
Associate Professor, Beckman Institute for Advanced Science and Technology
Walters, J. M., Kim, E. C., Zhang, J., Jeong, H. G., Bajaj, A., Baculis, B. C., Tracy, G. C., Ibrahim, B., Christian-Hinman, C. A., Llano, D. A., Huesmann, GR., & Chung, H. J. (2022). Pharmacological inhibition of STriatal-Enriched protein tyrosine Phosphatase by TC-2153 reduces hippocampal excitability and seizure propensity. Epilepsia, 63(5), 1211-1224. https://doi.org/10.1111/epi.17192
Kandel, M. E., Kim, E., Lee, Y. J., Tracy, G., Chung, H. J., & Popescu, G. (2021). Multiscale Assay of Unlabeled Neurite Dynamics Using Phase Imaging with Computational Specificity. ACS Sensors, 6(5), 1864-1874. https://doi.org/10.1021/acssensors.1c00100
Kim, E. C., Zhang, J., Tang, A. Y., Bolton, E. C., Rhodes, J. S., Christian-Hinman, C. A., & Chung, H. J. (2021). Spontaneous seizure and memory loss in mice expressing an epileptic encephalopathy variant in the calmodulin-binding domain of Kv7.2. Proceedings of the National Academy of Sciences, 118(51), [e2021265118]. https://doi.org/10.1073/pnas.2021265118
Pant, S., Zhang, J., Kim, E. C., Lam, K., Chung, H. J., & Tajkhorshid, E. (2021). PIP2-dependent coupling of voltage sensor and pore domains in Kv7.2 channel. Communications biology, 4(1), . https://doi.org/10.1038/s42003-021-02729-3
Urrutia, J., Aguado, A., Gomis-Perez, C., Muguruza-Montero, A., Ballesteros, O. R., Zhang, J., Nuñez, E., Malo, C., Chung, H. J., Leonardo, A., Bergara, A., & Villarroel, A. (2021). An epilepsy-causing mutation leads to co-translational misfolding of the Kv7.2 channel. BMC biology, 19(1), . https://doi.org/10.1186/s12915-021-01040-1