524 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)
Baculis BC*, Weiss AC*, Pang W*, Jeong HG, Lee JH, Liu DC, Tsai NP, and Chung HJ (2017). Prolonged seizure activity causes caspase dependent cleavage and dysfunction of G-protein activated inwardly rectifying potassium channels. Scientific Reports, 2017 Sep 26;7(1):12313. PMID: 28951616
Liu DC, Seimetz J, Lee KY, Kalsotra A, Chung HJ, Lu H, and Tsai NP (2017). Mdm2 mediates FMRP- and Gp1 mGluR-dependent protein translation and neural network activity. Human Molecular Genetics, ddx276, https://doi.org/10.1093/hmg/ddx276
Jang SS, Jeong H, Chung HJ (2017). Electroconvulsive seizures in rats and fractionation of their hippocampi to examine seizure-induced changes in postsynaptic density proteins. Journal of Visualized Experiments, 2017 Aug 15;(126). doi: 10.3791/56016. PMID:28829421
Zhu J, Lee KY, Jewett KA, Man H, Chung HJ, Tsai N-P- (2017). Epilepsy-associated gene Nedd4-2 mediates neuronal network activity and seizure susceptibility through AMPA receptors.PLOS Genetics, 2017 Feb 17;13(2):e1006634, PMID:28212375
Vega L JC, Lee MK, Qin EC, Lee KY, Chung HJ, Leckband DE, Kong H (2016). Three dimensional conjugation of recombinant N-Cadherin to a hydrogel for in vitro anisotropic neural growth. Journal of Materials Chemistry B Materials for Biology and Medicine, 4(42):6803-6811. PMCID: PMC5423733
Jang SS*, Royston SE*, Lee G#, Wang S#, and Chung HJ (2016). Seizure-induced regulations of amyloid-beta, STEP61, and STEP61 substrates involved in hippocampal synaptic plasticity. Neural Plasticity, 2016:2123748. PMCID: PMC4835651.
Jang SS*, Royston SE*, Xu J, Cavaretta JP, Vest MO, Lee KY, Lee S, Jeong H, Lombroso PJ, and Chung HJ(2015). Regulation of STEP61 and tyrosine-phosphorylation of NMDA and AMPA receptors during homeostatic synaptic plasticity. Molecular Brain, 8(1):55. PMCID: PMC4578242.
Lee K*, Royston SE*, Vest MO, Ley DJ, Lee S, Bolton EC, and Chung H (2015). (*These authors contributed equally). N-methyl-D-aspartate Receptors mediate Activity-dependent Down-Regulation of Potassium Channel Genes during the Expression of Homeostatic Intrinsic Plasticity. Molecular Brain. 8(1):4.
Wang Y, Cai E, Rosenkranz T, Ge P, Teng KW, Lim SJ, Smith A, Chung HJ, Sachs F, Sachs F, Green W, Gottlieb P, and Selvin PR (2014). Small Quantum Dots Conjugated to Nanobodies as Immunofluorescence Probes for Nanometric Microscopy. Bioconjugate Chemistry. 25(12):2205-11.
Wang Y, Cai E, Rosenkranz T, Ge P, Teng KW, Chung HJ, Sachs F, Gottlieb P, and Selvin PR (2014). Stable small quantum dots for synaptic receptor tracking on live neurons. Angewandte Chemie, 53(46):12484-8.
Lee KY and Chung HJ (2014). NMDA receptors and L-type voltage-gated Ca2+ channels mediate the expression of bidirectional homeostatic intrinsic plasticity in cultured hippocampal neurons. Neuroscience, (277):610-23.
Cavaretta JP*, Sherer KS*, Lee KY, Issema RS, Kim EH, and Chung HJ (2014). (*These authors contributed equally). Polarized Axonal Surface Expression of Neuronal KCNQ Potassium Channels is Regulated by Calmodulin Interaction with KCNQ2 Subunit. PLos One, 9(7):e103655. DOI:10.1371/journal.pone.0103655.
Chung HJ (2014). Role of calmodulin in neuronal Kv7/KCNQ potassium channels and epilepsy. Frontiers in Biology. 9(3):205-15.
Vega L JC, Lee MK, Jeong JH, Smith CE, Lee KY, Chung HJ, Leckband DE, Kong H. (2014). Recapitulating cell-cell adhesion using N-Cadherin biologically tethered to substrates. Biomacromolecules 15(6):2172-9.
Hearing M, Kotecki L, Marron Fernandez de Velasco E, Fajardo-Serrano A, Chung HJ, Luján R, Wickman K. (2013). Repeated Cocaine Weakens GABAB-Girk Signaling in Layer 5/6 Pyramidal Neurons in the Prelimbic Cortex. Neuron 80(1):159-70
Chung HJ*, Lee HK* (2009). Constructing a road map from synapses to behaviour. Meeting on Synapses: From Molecules to Circuits & Behavior. (*These authors contributed equally to this work). EMBO Rep.,10(9):958-62. PubMed Central [PMCID2750071]
Chung HJ*, Woo-ping Ge*, Xiang Qian, Ofer Wiser, Jan YN, and Jan LY (2009). G-protein activated inwardly rectifying potassium channels mediate depotentiation of long-term potentitation. (*These authors contributed equally to this work). Proc Natl Acad Sci U S A, 106(2): 635-40.
Chung HJ, Xiang Qian, Melissa Ehlers, Jan YN, and Jan LY (2009). Neuronal activity regulates phosphorylation-dependent surface delivery of G-protein activated inwardly rectifying potassium channels. Proc Natl Acad Sci U S A, 106(2): 629-34.
Chung HJ, Jan YN, and Jan LY (2006). Impaired polarized surface expression of neuronal KCNQ channels as a mechanism for benign familial neonatal convulsion. Proc Natl Acad Sci U S A, 103 (23): 8870-5
Chung HJ, Lau LF, Huang YH and Huganir RL (2004). Regulation of NMDA Receptor complex and trafficking by activity-dependent phosphorylation of NR2B subunit PDZ ligand. J Neurosci, 24(45):10248-59.
Heynen AJ, Yoon BJ, Liu CH, Chung HJ, Huganir RL and Bear MF (2003). Molecular mechanism for loss of visual cortical responsiveness following brief monocular deprivation. Nat Neurosci. 6(8):854-62.
Chung HJ*, Steinberg JP*, Huganir RL, Linden DJ (2003). Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. (*These authors contributed equally to this work). Science, 300(5626):1751-5.
McDonald BJ, Chung HJ, and Huganir RL (2001). Identification of Protein Kinase C phosphorylation sites within the AMPA receptor GluR2 subunit. Neuropharmacology, 41(6):672-679
Kim CH*, Chung HJ*, Lee H-K-, and Huganir RL (2001). Interaction of the AMPA receptor subunit GluR2/3 with PDZ domains regulates hippocampal long term-depression. (*These authors contributed equally to this work). Proc Natl Acad Sci U S A, 98(20):11725-30
Xia J, Chung HJ, Wihler C, Huganir RL, and Linden DJ (2000). Cerebellar long-term depression requires PKC-regulated interactions between GluR2/3 and PDZ domain-containing proteins. Neuron, 28(2):499-510.
Chung HJ, Xia J, Scannevin RH, Zhang X, and Huganir RL (2000). Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins. J Neurosci, 20(19):7258-67.
Baculis, B. C., Kesavan, H., Weiss, A. C., Kim, E. H., Tracy, G. C., Ouyang, W., Tsai, N. P., & Chung, H. J. (2022). Homeostatic regulation of extracellular signal-regulated kinase 1/2 activity and axonal Kv7.3 expression by prolonged blockade of hippocampal neuronal activity. Frontiers in Cellular Neuroscience, 16, . https://doi.org/10.3389/fncel.2022.838419
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