Disruption of the Epilepsy KCNQ2 Gene Results in Neural Hyperexcitability


  • Hirotaka Watanabe,

  • Eiichiro Nagata,

  • Arifumi Kosakai,

  • Motonao Nakamura,

  • Masahiro Yokoyama,

  • Kortaro Tanaka,

  • Hitoshi Sasai

  • The first two authors contributed equally to this work.

  • Abbreviations used : BFNC, benign familial neonatal convulsion ; dpc, days postcoitus ; ES, embryonic stem ; PTZ, pentylenetetrazole.

Address correspondence and reprint requests to Dr. H. Sasai at Pharmaceutical Frontier Research Laboratories, Japan Tobacco, Inc., 13-2, Fukuura 1-chome, Kanazawa-Ku, Yokohama, Kanagawa, 2360004, Japan. E-mail : hitoshi.sasai@ims.jti.co.jp


Abstract : Benign familial neonatal convulsion (BFNC) is a common idiopathic epilepsy with autosomal dominant inheritance. Recently, two novel voltage-dependent potassium channel genes, KCNQ2 and KCNQ3, were identified by positional cloning as being responsible for BFNC. Heterotetramers of the products of these genes form M-channels and regulate the threshold of electrical excitability of neurons. We disrupted the mouse KCNQ2 gene via gene targeting to study the relationship between KCNQ2 and epilepsy. Homozygous pups (KCNQ2 -/-) died within a few hours after birth owing to pulmonary atelectasis that was not due to the status of epileptic seizures, although their development was morphologically normal. Heterozygous mice had decreased expression of KCNQ2 and showed hypersensitivity to pentylenetetrazole, an inducer of seizure. These data indicate that the decreased expression of KCNQ2 might cause a hyperexcitability of the CNS, which accounts for the mechanism of BFNC.