427A Burrill Hall
Office: (217) 244-6839
Lab: (217) 244-6294
Fax: (217) 333-1133
Mail to: Department of Molecular and Integrative Physiology
524 Burrill Hall
407 South Goodwin Avenue,
Urbana, IL 61801
Hee Jung Chung
Assistant Professor of Molecular and Integrative Physiology
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
Activity-dependent regulation of ion channels in Neural Plasticity
How does the brain acquire, process, and store information? Neurons perform these integral functions of the brain by conducting electrical signals generated by the movement of ions through ion channels in their functionally and morphologically distinct subcellular compartments: axons and dendrites. Axons deliver information to other neurons in the form of electrical nerve impulses (action potentials) whereas dendrites receive information from axons of other neurons in the form of neurotransmitters at specialized cell-cell junctions called synapses (synaptic transmission).
Activity-dependent persistent changes in synaptic transmission (synaptic plasticity) as well as action potential/intrinsic excitability (intrinsic plasticity) are thought to provide the cellular basis for information processing and storage in the brain. Abnormal synaptic and intrinsic plasticity have been implicated in not only mental retardation and learning deficits but also neurological disorders and diseases. Thus it is important to understand the molecular and cellular mechanisms of synaptic and intrinsic plasticity.
Given that ion channels are essential for neuronal function in generating and modulating synaptic transmission and action potential, the main research goal of my laboratory is to understand how persistent functional changes in ion channels contribute to synaptic and intrinsic plasticity under physiologic and pathologic conditions, and ultimately animal behavior.
Specifically, my lab is working on the following three areas using interdisciplinary approaches including primary neuronal culture, live and fixed microscopy, biochemistry, electrophysiology, and mouse genetics.
(1) What are the molecular mechanism and physiological role of GIRK channels in synaptic plasticity?
Synaptic plasticity such as long term potentiation (LTP) and depotentiation is thought to underlie the cellular basis for behavioral and cognitive functions. LTP is a long-lasting increase in excitatory synaptic strength whereas depotentiation is the reversal of LTP. Compared to the extensive studies on the molecular mechanisms of LTP and its involvement in animal behavior such as learning and memory, very little is known about the molecular mechanism and physiological role of depotentiation. My recent research has uncovered a novel finding that depotentiation but not LTP requires G-protein activated inwardly rectifying potassium channels (GIRK) (Chung et al., 2009b), a critical mediator of neuronal inhibition by neurotransmitters and neuromodulators. My lab is currently investigating how activity-dependent regulation of GIRK channels (Chung et al., 2009a) contributes to depotentiation. A better understanding of the molecular mechanism of depotentiation may lay further foundation for developing animal models to specifically test the role of depotentiation in behavior (learning and memory) and disease.
(2) What are the molecular mechanism and physiological role of KCNQ channels in intrinsic plasticity?
Compared to the extensive knowledge on synaptic plasticity, very little is known about the molecular players and mechanisms of intrinsic plasticity. I have recently identified a number of ion channels that exhibit activity-dependent changes in their function, which may likely contribute to the expression of intrinsic plasticity. One of the ion channels I have identified is voltage-gated KCNQ potassium channel that inhibits repetitive firing of action potential. My lab is currently investigating how activity-dependent regulation of KCNQ channels is achieved and how such regulation contributes to intrinsic plasticity. Given that these channels are preferentially targeted to axon and that their impaired axon targeting may serve as one of pathomechanisms underlying benign familial neonatal convulsions (BFNC), a dominantly-inherited epilepsy (Chung et al., 2006), a better understanding of activity-dependent regulation of KCNQ channels may allow us to provide novel mechanistic and functional insights into intrinsic plasticity implicated in behavior (learning and memory), aging, and disease (pain, epilepsy).
(3) What are the molecular mechanism and physiological role of STEP in homeostatic plasticity?
Homeostatic plasticity encompasses dynamic regulatory mechanisms by which neurons maintain their excitability and synaptic strength within physiological limits. While the failure of this plasticity likely contributes to the pathogenesis of hyperexcitability-associated disorders including epilepsy, the molecular basis of this important plasticity has yet to be elucidated. This homeostatic synaptic plasticity requires transcription, suggesting that regulation of gene expression mediates its induction. From our unbiased gene expression profiling in hippocampal neuronal culture, we identified striatal-enriched protein tyrosine phosphatase (STEP) whose expression is altered during homeostatic plasticity. Since STEP is shown to oppose synaptic strength by dephosphorylating AMPA and NMDA receptors and promoting their internalization, my lab is currently investigating the extent to which activity-regulated STEP contributes to homeostatic synaptic plasticity. Given that STEP dysregulation is implicated in epilepsy and epilepsy-associated diseases that cause lasting cognitive and psychiatric impairments, the new knowledge on activity-dependent regulation of STEP and its potential roles in homeostatic synaptic plasticity may lay a firm foundation for exploring STEP as a novel therapeutic target for epilepsy that could fine-tune synaptic homeostasis.
Basil O'Connor Starter Scholar Research Award, March of Dimes Foundation
Young Investigator Award, Roy J. Carver Charitable Trust
Targeted Research Initiative for Severe Symptomatic Epilepsies Grant Award, Epilepsy Foundation
Lee KY*, Royston SE*, Vest MO, Ley DJ, Kim EH, Jan LY, and Chung HJ (2013). (*These authors contributed equally). NMDA Receptors and L-type Ca2+ Channels Mediate Activity-Dependent Regulation of K+ Channel Genes during the Expression of Homeostatic Intrinsic Plasticity. J Neurosci, Under revision.
Cavaretta JP*, Sherer KS*, Lee KY, Issema RS, Kim EH, and Chung HJ (2013). (*These authors contributed equally). Polarized Axonal Surface Expression of Neuronal KCNQ Potassium Channels is Regulated by Calmodulin Interaction with KCNQ2 Subunit. PLos One , Under revision.
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.