Loss of Pre-Inspiratory Neuron Synchroneity in Mice with DSCAM Deficiency
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 hours after birth. Whole body plethysmography showed irregular respiration and lower ventilatory response to hypercapnia in the null mutants. Further, 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 (Pre-I) neurons located in the rostral ventrolateral medulla (RVLM) 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. These results have been published (Amano et al. 2009).
KeywordsDown Syndrome Facial Nerve Activity Facial Nucleus Rostral Ventrolateral Medulla Ventral Medulla
1 Neonatal Death of Dscam-Deficient Mouse
Cell adhesion molecules of the neural Ig superfamily mediate a variety of cell-cell interactions that are important for neural development and function. We previously identified the DSCAM gene on human chromosome 21q22 and proposed it as an intriguing candidate gene for the etiology of Down syndrome (Yamakawa et al. 1998). To explore the physiological functions of DSCAM protein, we generated Dscam-deficient mice (Amano et al. 2009). The heterozygous knockout (Dscam +/−) mice were fertile and developed almost normally. Matings of heterozygotes (Dscam +/−) yielded homozygotes (Dscam -/-). Populations of pups for each genotype were in accordance with the expected Mendelian distribution. This indicates that deficiency of DSCAM does not lead to embryonic lethality. However, a majority of the null mutant mice (Dscam -/-) died within 24 hours after birth.
2 Dscam-/- Mice Show Irregular Central Respiratory Activities
3 Pre-I Neuron Activity is Deficient in Dscam-/- Mouse
Pre-I neuron activity has been reported to correlate with facial nerve activity in the newborn rat brainstem-spinal cord preparation (Onimaru et al. 2006). We therefore investigated the output of the facial nerve activity together with C4 inspiratory activity in Dscam -/- and wild-type mice using the preparation with more rostral anterior limit (open arrow in Fig. 2A) in order to keep the facial nucleus intact. In wild-type mice, the activities of the facial nerve were regular, constantly phasic, and roughly synchronized with their C4 inspiratory activities (n = 6), while that of Dscam -/- mice became tonic and lost their synchroneity to the C4 activities (n = 5) (Fig. 2 M).
4 Enlarged Medulla of Dscam-/- Mouse
In the present study, we found that Dscam deficiency in mice leads to death shortly after birth with central respiratory defects. Physiological analysis revealed that the synchroneity of Pre-I neurons was reduced in Dscam +/− mouse and lost in Dscam -/- mouse, whereas that of Insp neurons in Dscam +/− and Dscam -/- mice was essentially retained. These results indicate that Dscam deficiency in mice leads to specific defects in central respiratory regulation, and make DSCAM an interesting candidate gene for central respiratory disorders. Furthermore, it would be plausible that the overexpression of DSCAM on chromosome 21q22 could contribute to some of neurodevelopmental defects in patients with Down syndrome, such as their central nervous system-dependent respiratory defects (Ferri et al. 1997; Ferri et al. 1998) and/or mental retardation itself.
This work was partly supported by a grant from RIKEN Brain Science Institute, Grant-in-Aid for Scientific Research (KAKENHI) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology. We thank Dr. T. Takeuchi, N. Nishiyama, and Y. Onodera for technical support, Dr. K. Yamaguchi for helpful suggestions.
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