Research Focus

Research Interests

  1. Identification of pathogenic mechanisms for epilepsy mutations in Kv7 channels

Neuronal Kv7/KCNQ channels are voltage-gated potassium channels composed of Kv7.2 and Kv7.3 subunits. Enriched on the plasma membrane of axons (Chung et al., 2006), they potently inhibit repetitive and burst firing of action potentials. Whereas Kv7 activators are used as anti-epileptic drugs, mutations in Kv7 cause benign familial neonatal convulsion and severe epileptic encephalopathy. Despite more than 100 documented epilepsy mutations of Kv7, their precise pathogenic mechanisms remain largely elusive.  

Chung lab focuses on investigating mechanism underlying axonal enrichment of Kv7 channels and Kv7-related epilepsy. My laboratory has reported calmodulin binding to helix A of Kv7.2 is critical for targeting of Kv7 potassium channels to the axons, and their ability to suppress neuronal excitability (Cavaretta et al., 2014).

Our recent research revealed that epileptic encephalopathy mutations are sginificantly clustered in helix B of Kv7.2, and cause multiple dysfunction of Kv7 channels including voltage-dependent activation, axonal localization, and interaction with calmodulin and PIP2, leading to neuronal hyperexcitability (Kim et al., submitted; Zhang et al, in preparation). 

Chung lab is actively investigating how axonal targeting of Kv7 is achieved and regulated by epilepsy mutations, and how such targeting impacts excitability. We hope to employ high resolution single molecule imaging using a new series of quantum dots (QDs) with highly compact sizes between 7-10 nm which were developed by our collaborators, Dr. Selvin and Dr. Smith (Cai et al., 2014; Wang et al., 2014). In addition, we are developing knock-in mice to study pathogenesis of select epilepsy mutations in vivo. This study will increase our understanding of these “unexplored” mechanisms, and facilitate the development of new therapy for epilepsy by enhancing Kv7 surface density.

  1. Identification of molecular mechanisms underlying homeostatic intrinsic plasticity

Electrical properties of neuronal membranes can undergo persistent modification in response to neuronal activity or sensory experience. Homeostatic plasticity is one such mechanism by which neurons adapt their electrical activity within a physiologic range based on their previous activity. For example, a 2-day blockade of neuronal activity in the hippocampus leads to compensatory increase in neuronal communication at synapses (termed synaptic transmission) as well as the ability of hippocampal neurons to fire action potentials at a given input signal (termed intrinsic excitability). Interestingly, activity blockade in the hippocampus for 2-4 weeks leads to temporal lobe epilepsy in rodents.

These findings raise a compelling question: “when and how do neurons exploit homeostatic plasticity to stabilize their network as a normal adaptive response, or to cause persistent neuronal hyperexcitability as a pathological manifestation in epilepsy?” To answer this question, we must first understand how homeostatic plasticity is induced in the normal brain. Whereas much has been learned about homeostatic regulation of synaptic transmission (homeostatic synaptic plasticity), our knowledge of homeostatic regulation of intrinsic excitability (homeostatic intrinsic plasticity) remains largely unknown.

Chung lab 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 873 genes whose protein products could potentially mediate homeostatic plasticity (Lee et al., 2015). We reported that homeostatic increases in hippocampal excitability are associated with repression of multiple potassium channel genes and a decrease in total potassium current, including the currents through axonal potassium channels (Lee et al., 2015).

Chung lab is actively developing novel transgenic mouse lines in which activity blockade can be induced in hippocampal neurons without involving invasive surgical methodologies. These mice will be useful in investigating the potentially link between homeostatic plasticity and epileptogenesis caused by chronic activity blockade.

  1. Identification of novel players in neuronal hyperexcitability diseases

Chung lab discovered PTPN5 from gene expression profiling. PTPN5 encodes STriatal-Enriched protein tyrosine Phosphatase (STEP61). Although STEP61 is known to weaken synapses by dephosphorylating and inactivating synaptic glutamate receptors, its role in homeostatic synaptic plasticity was unknown. We discovered that 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 reported that a single acute episode of electroconvulsive seizures (ECS) increases expression of STEP61, amyloid-β (Aβ), and its precursor protein and decreases tyrosine phosphorylation of NMDA receptors (Jang et al., 2016), suggesting that elevated expression of STEP61 and Aβ may contribute to compensatory weakening of synaptic strength in response to seizures. Recently, we identified that kainite-induced status epilepticus is associated with caspase-dependent cleavage and down-regulation of GIRK potassium channels (Baculis et al., 2017).

Chung lab is actively studying the roles that STEP61 , GIRK channels, and Aβ  in drug-resistant seizures in  temporal lobe epilepsy (TLE), which are associated with sclerosis at or close to the seizure foci. Specifically, we are investigating if progressive hippocampal sclerosis and encephalopathy of TLE is due to pathologic accumulation of Aβ and STEP61 and caspase-dependent cleavage of GIRK channels in the rodent models of TLE. In addition, we are also interested in delineating the mechanisms underlying hyperexcitability in early stage of Alzheimer’s disease (AD). These studies will provide insights into pathogenesis of TLE and AD, and novel targets as possible biomarkers and/or therapeutic targets for TLE and AD.