Cellular physiology of epilepsy-associated KCNQ2 channels

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DESCRIPTION (provided by applicant): The KCNQ channel family includes five genes, known as Kcnq1-5. Most family members are required for proper function of either the nervous or cardiovascular system as loss of function mutations in Kcnq genes lead to LQTS syndrome (Kcnq1), progressive hearing loss (Kcnq4) and benign familial neonatal convulsions (BFNC), a pediatric epilepsy (Kcnq2, Kcnq3). KCNQ2/3 heteromeric channels are thought to mediate the M-current, a sub-threshold activating potassium conductance that controls the excitability of CNS neurons. However, unlike KCNQ3 channels, more than 90% of mutations related to the BFNC are mapped to the Kcnq2 gene locus and Kcnq2 knockout mice die within 24 hours after birth. Thus, Kcnq2 may either be the primary KCNQ subunit in the brain or it may play a unique role in additional physiological processes. Our long-term goal is to understand the in vivo functions of KCNQ channels and how mutations in these channels lead to epileptogenesis. The overall goal of this project is to determine the role of KCNQ2 channels in controlling intrinsic neuronal excitability. To achieve our objective we will combine pharmacology, protein engineering, genetics, and electrophysiology. Using these approaches we will first establish the functional contribution of KCNQ2 channels to the M-current across development using a recently identified KCNQ2-specific inhibitor. We will subsequently test whether KCNQ2 channels underlie multiple conductances in the brain using gain-of-function mutations and novel pharmacology. Lastly, we will test the role of KCNQ2 channels in regulating resting and active membrane properties using Kcnq2 conditional knockout mice. These studies will be conducted in mouse brain slices using current- and voltage-clamp recordings. We will use hippocampus as a model brain area because it is implicated in epilepsy and learning and memory. The results from these studies will provide insight into an important potassium channel that plays a fundamental role in limiting unchecked neuronal activity and seizures in the brain. PUBLIC HEALTH RELEVANCE: Dysfunction of the potassium channel KCNQ2 leads to the pediatric epilepsy benign familial neonatal convulsions, but the mechanisms by which these channels affect neuronal activity are not well-understood. Our goal is to unravel the precise physiological role KCNQ2 channels play in the normal brain. Such work will provide an improved understanding of innate mechanisms that prevent epileptogenesis and could lead to the development of novel anti-epileptic drugs.