Potassium (K+) channels serve diverse and critical roles in neuronal signaling and mutations in K+ channel genes have been linked to human neurological diseases such as epilepsy. Nevertheless, significant gaps still exist in our understanding of how K+ channels control neuronal excitability. For example, the Kv12 gene family is among the oldest and most highly conserved K+ channel families, yet the physiological function of these channels has not previously been examined in vivo due to a lack of genetic and pharmacologic tools. To address this knowledge gap, we have generated a mouse knockout of the voltage-gated K+ channel Kv12.2. The knockout mice have spontaneous epilepsy and a pronounced sensitivity to the chemoconvulsant pentylenetetrazol, suggesting a key role for Kv12.2 in the regulation of neuronal excitability. We find that hippocampal pyramidal neurons cultured from Kv12.2 knockout mice have significantly depolarized resting potentials, high input resistance and low spike thresholds. Spontaneous firing rates in these knockout neurons are ~10-fold higher than in WT neurons. The goal of this research project is to determine how Kv12.2 controls excitability in neurons and circuits, and to determine how loss of Kv12.2 leads to epilepsy. This will be accomplished through a combination of genetic, biochemical, pharmacological and electrophysiological approaches. The research will provide valuable new insights into the control of neuronal firing and will provide a critical assessment of the value of Kv12.2 as a therapeutic target for antiepileptic drugs.

Public Health Relevance

We have developed a novel and unique animal model of epilepsy by knocking out the potassium channel Kv12.2 in the mouse. The research in this proposal is designed explore the role of Kv12.2 in neuronal signaling in order to understand how loss of this potassium channel leads to seizure susceptibility and epilepsy. This research will provide valuable new insights into mechanisms of seizure control and thus addresses a critical need for new clinical strategies for the control of epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS069842-05
Application #
8416417
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Whittemore, Vicky R
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$304,929
Indirect Cost
$98,057
Name
Pennsylvania State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Martinson, Alexandra S; van Rossum, Damian B; Diatta, Fortunay H et al. (2014) Functional evolution of Erg potassium channel gating reveals an ancient origin for IKr. Proc Natl Acad Sci U S A 111:5712-7
Kazmierczak, Marcin; Zhang, Xiaofei; Chen, Bihan et al. (2013) External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor. J Gen Physiol 141:721-35
Zhang, Xiaofei; Bertaso, Federica; Yoo, Jong W et al. (2010) Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nat Neurosci 13:1056-8