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.