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The Journal of Neuroscience, March 4, 2009, 29(9):2984-2996; doi:10.1523/JNEUROSCI.3624-08.2009

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Behavioral/Systems/Cognitive
DSCAM Deficiency Causes Loss of Pre-Inspiratory Neuron Synchroneity and Perinatal Death

Kenji Amano,¹ Morimitsu Fujii,² Satoru Arata,⁷ Takuro Tojima,³ Masaharu Ogawa,⁴ Noriyuki Morita,⁵ Atsushi Shimohata,¹ Teiichi Furuichi,⁵ Shigeyoshi Itohara,⁶ Hiroyuki Kamiguchi,³ Julie R. Korenberg,⁸ Akiko Arata,^2,9 and Kazuhiro Yamakawa¹

Laboratories for ¹Neurogenetics, ²Memory and Learning, ³Neuronal Growth Mechanisms, ⁴Cell Culture Development, ⁵Molecular Neurogenesis, and ⁶Behavioral Genetics, RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan, ⁷Center for Biotechnology, Showa University, Shinagawa-ku, Tokyo 142-8555, Japan, ⁸The Brain Institute, University of Utah, Salt Lake City, Utah 84108, and ⁹Division of Physiome, Department of Physiology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan

Correspondence should be addressed to either of the following: Dr. Kazuhiro Yamakawa, Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan, Email: yamakawa{at}brain.riken.jp; or Dr. Akiko Arata, Division of Physiome, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501, Japan, Email: akoarata{at}hyo-med.ac.jp or Email: ako{at}brain.riken.jp

Down syndrome cell adhesion molecule (DSCAM) is a neural adhesion molecule that plays diverse roles in neural development. We disrupted the Dscam locus in mice and found that the null mutants (Dscam^–/–) died within 24 h after birth. Whole-body plethysmography showed irregular respiration and lower ventilatory response to hypercapnia in the null mutants. Furthermore, a medulla–spinal cord preparation of Dscam^–/– mice showed that the C4 ventral root activity, which drives diaphragm contraction for inspiration, had an irregular rhythm with frequent apneas. Optical imaging of the preparation using voltage-sensitive dye revealed that the pre-inspiratory neurons located in the rostral ventrolateral medulla and belonging to the rhythm generator for respiration, lost their synchroneity in Dscam^–/– mice. Dscam^+/– mice, which survived to adulthood without any overt abnormalities, also showed irregular respiration but milder than Dscam^–/– mice. These results suggest that DSCAM plays a critical role in central respiratory regulation in a dosage-dependent manner.

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Received July 31, 2008; revised Jan. 15, 2009; accepted Jan. 17, 2009.

Correspondence should be addressed to either of the following: Dr. Kazuhiro Yamakawa, Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan, Email: yamakawa{at}brain.riken.jp; or Dr. Akiko Arata, Division of Physiome, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501, Japan, Email: akoarata{at}hyo-med.ac.jp or Email: ako{at}brain.riken.jp

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