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.
Abstract In an excised Wistar rat medulla‐spinal cord block preparation we previously found that dopamine slows respiratory rhythm by activation of dopamine D 4 receptors [ Fujii et al ., (2004) Neurosci. Res. , 50, 355–359.] In the present paper, we investigated the effect of dopamine on pre‐inspiratory (Pre‐I) and inspiratory (I) neurons using the combination of an optical recording technique with a voltage‐sensitive dye, unit recording and patch‐clamp recording. Optical imaging of the ventral surface of the block preparation disclosed different locations and activity patterns of Pre‐I and I neurons. In addition to slowing the rhythm, dopamine depressed respiratory activity of Pre‐I neurons collectively but not that of I neurons. The dopaminergic suppression of Pre‐I neurons was mimicked by a dopamine D 4 receptor agonist, PD168077. Unit recording and patch‐clamp recording demonstrated that dopamine depolarizes Pre‐I neurons, disperses Pre‐I firing and depresses Pre‐I phase postsynaptic potentials (PSPs) of I neurons. Immunohistological investigation revealed that Pre‐I neurons express dopamine D 4 receptors. We found that approximately 60% of Pre‐I neurons express dopamine D 4 receptors. These results show that dopaminergic respiratory rhythm depression is due to dispersion of synchronized Pre‐I driving of I neurons caused by dopamine D 4 receptor stimulation of Pre‐I neurons.
