Developmental changes of serotonin 4(a) receptor expression in the rat pre‐Bötzinger complex

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Abstract
Serotonin receptors (5‐HTRs) are known to be involved in the regulation of breathing behavior and to mediate neurotrophic actions that exert a significant function in network formation during development. We studied neuronal 5‐HT4(a)R‐immunoreactivity (‐IR) at developmental ages from E14 to P10. Within the pre‐Bötzinger complex (pre‐BötC), a part of the respiratory network important for rhythmogenesis, 5‐HT4(a)R‐IR was most extensive in rats at an age of E18. The 5‐HT4(a)‐IR was found predominantly in the neuropil, whereas somatic staining was sporadic at late embryonic (E18–E20) stages. At birth, we observed a dramatic change to a predominantly somatic staining, and neuropil staining was greatly reduced and disappeared at an age of P4. In all developmental stages, 5‐HT4(a) and μ‐opioid receptors were strongly coexpressed in neurons of the pre‐BötC, whereas 5‐HT4(a)R expression was absent in neurons within the dorsal horn. Nestin, a marker for CNS progenitor cells, was used to obtain information about the degree of pre‐BötC differentiation. Nestin‐positive cells did not appear within the pre‐BötC before age E20. At E16, nestin‐expressing cells were absent in the nucleus ambiguus (NA) and its ventral periphery. The number of nestin‐positive cells increased after birth within and outside the pre‐BötC, the majority of cells being glial. Coexpression of nestin and 5‐HT4(a)R was localized predominantly within the NA and appeared only sporadically within the pre‐BötC. We conclude that 5‐HT4(a)Rs are important not only for neuromodulation of cellular excitability but also for respiratory network formation. J. Comp. Neurol. 506:775–790, 2008.