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The Journal of Neuroscience, November 24, 2004, 24(47):10693-10701; doi:10.1523/JNEUROSCI.2909-04.2004

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Behavioral/Systems/Cognitive
Malfunction of Respiratory-Related Neuronal Activity in Na⁺, K⁺-ATPase 2 Subunit-Deficient Mice Is Attributable to Abnormal Cl^- Homeostasis in Brainstem Neurons

Keiko Ikeda,¹ Hiroshi Onimaru,³ Junko Yamada,⁴ Koichi Inoue,⁵ Shinya Ueno,⁵ Tatsushi Onaka,² Hiroki Toyoda,¹ Akiko Arata,⁶ Tomo-o Ishikawa,^7,8 Makoto M. Taketo,^7,8 Atsuo Fukuda,^4,5 and Kiyoshi Kawakami¹

¹Division of Biology, Center for Molecular Medicine, and ²Department of Physiology, Jichi Medical School, Kawachi, Tochigi 329-0498, Japan, ³Department of Physiology, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8555, Japan, ⁴Department of Biological Information Processing, Graduate School of Electronic Science and Technology, Shizuoka University, Hamamatsu, Shizuoka 432-8011, Japan, ⁵Department of Physiology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan, ⁶Laboratory for Memory and Learning, Brain Science Institute, RIKEN (Institute of Physical and Chemical Research), Wako-shi, Saitama 351-0198, Japan, ⁷Department of Pharmacology, Graduate School of Medicine, Kyoto University, Sakyo, Kyoto 606-8501, Japan, and ⁸Banyu Tsukuba Research Institute (Merck), Tsukuba, Ibaragi 300-2611, Japan

Na⁺, K⁺-ATPase 2 subunit gene (Atp1a2) knock-out homozygous mice (Atp1a2^-/-) died immediately after birth resulting from lack of breathing. The respiratory-related neuron activity in Atp1a2^-/- was investigated using a brainstem-spinal cord en bloc preparation. The respiratory motoneuron activity recorded from the fourth cervical ventral root (C4) was defective in Atp1a2^-/- fetuses of embryonic day 18.5. The C4 response to electrical stimulation of the ventrolateral medulla (VLM) recovered more slowly in Atp1a2^-/- than in wild type during superfusion with Krebs' solution, consistent with the high extracellular GABA in brain of Atp1a2^-/-. Lack of inhibitory neural activities in VLM of Atp1a2^-/- was observed by optical recordings. High intracellular Cl^- concentrations in neurons of the VLM of Atp1a2^-/- were detected in gramicidin-perforated patch-clamp recordings. The 2 subunit and a neuron-specific K-Cl cotransporter KCC2 were coimmunoprecipitated in a purified synaptic membrane fraction of wild-type fetuses. Based on these results, we propose a model for functional coupling between the Na⁺, K⁺-ATPase 2 subunit and KCC2, which excludes Cl^- from the cytosol in respiratory center neurons.

Key words: Na, K-ATPase; KCC2; respiratory neuron; brainstem-spinal cord preparation; [Cl^-]_i; GABA

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Received July 19, 2004; revised September 19, 2004; accepted October 19, 2004.

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