Serotonergic modulation of central respiratory activity in the neonatal mouse: an in vitro study.

In order to determine whether the serotonergic modulation of the central respiratory activity previously reported in neonatal rats occurs in species other than the rat, we performed identical in vitro experiments on the neonatal mouse to those performed on the neonatal rat. The effects of adding serotonin (5-hydroxytryptamine, 5-HT) and related agents to the superfusate suggested that the respiratory rhythm generator undergoes an excitatory modulation via medullary 5-HT1A receptors. Upon applying the drugs to the spinal cord alone, 5-HT was found to have a dual effect on phrenic motoneuron firing: (i) a facilitatory effect mediated by 5-HT2A receptors and (ii) a depressive effect on their inspiratory discharge mediated by non-5-HT1A, non-5-HT2A, non-5-HT3 receptors, possibly of the 5-HT1B subtype. It was therefore concluded that serotonin modulates the neonatal central respiratory activity in mice as well as in rats, and that similar 5-HT receptor subtypes are involved in this process in both species

Rostral ventrolateral medulla and respiratory rhythmogenesis in mice.

To compare the mechanisms governing perinatal respiratory rhythmogenesis in mice and rats, we adapted to the neonatal mouse the in vitro brainstem-spinal cord preparation of the neonatal rat. In mouse preparations retaining the pons, phrenic root did not show any rhythmic activity. Elimination of the pons induced phrenic rhythmic bursts which (1) induced respiratory chest movements (rib cage kept attached to the spinal cord), (2) were abolished by spinal cord transection, (3) could be prematurely induced by rostral ventro-lateral medulla (RVLM) stimulation, (4) occurred in phase with the bursting firing of RVLM neurons, and (5) were abolished by RVLM lesion. Then, the RVLM appears crucial for respiratory rhythmogenesis in both species; some results suggest however that vagal and pontine respiratory controls might not be identical in mice and rats

Serotonin levels are abnormally elevated in the fetus of the monoamine oxidase-A-deficient transgenic mouse.

Developmental changes in levels of serotonin, L-tryptophan and 5-hydroxyindol acetic acid (5-HIAA) were measured by high pressure liquid chromatography (HPLC) in the forebrain, brainstem and cervical cord of fetal, neonatal and adult mice from the wild strain C3H and the transgenic strain Tg8, created from the C3H line by the disruption of the gene encoding monoamine oxidase A. The results indicated that the absence of monoamine oxidase A activity in Tg8 mice results in abnormally high 5-hydroxytryptamine (5-HT) levels in all the central nervous structures and at all the studied developmental ages. Since serotonin levels were 4-5 times larger in Tg8 than in C3H mice at gestational day 20, comparing the central network function at birth of C3H and Tg8 neonates should shed some light on the role of serotonin in prenatal network maturation

Perinatal changes of I(h) in phrenic motoneurons.

The hyperpolarization-activated cationic current (I(h)) was characterized and its maturation studied on phrenic motoneurons (PMNs), from reduced preparations of foetal (E18 and E21) and newborn (P0-P3) rats, using the whole-cell patch-clamp technique. In voltage-clamp mode, 2-s hyperpolarizing steps (5-mV, -50 to -110 mV) elicited a noninactivating inward current, blocked by external application of Cs+ or ZD 7288. At -110 mV, Ih current density averaged 0.67 +/- 0.41 pA/pF at E18, reached a transient peak at E21 (1.38 +/- 0.11 pA/pF) and decreased at P0-P3 (0.77 +/- 0.22 pA/pF). V1/2 was similar at E18 and E21 (-79 mV) but was significantly hyperpolarized at P0-P3 (-90 mV). The time constant of activation was voltage-dependent, and significantly faster at E21. Reversal potential was similar at all ages when estimated by extrapolation or tail current procedures. It was positively shifted by 25 +/- 6 mV when external potassium was raised from 3 to 10 m M, suggesting a similar sensitivity to K+ from E18 to P0-3. Cs(+) or ZD 7288 applications on PMNs at rest in current-clamp mode, in a partitioned chamber, induced a 10 +/- 2 mV hyperpolarization at E18 and E21, and an 8 +/- 2 mV hyperpolarization at P0-3. The area of the central respiratory drive potential or current was increased by 33 and 31%, respectively, at E21, but was not significantly modified at E18 and P0-3. Our data suggest a critical period during the perinatal maturation of Ih during which it is transiently upregulated and attenuates the influence of the central respiratory drive on PMNs just prior to birth

Serotonergic inhibition of phrenic motoneuron activity: an in vitro study in neonatal rat.

In vitro experiments were conducted on neonatal rat brainstem-spinal cord preparations to test the hypothesis of an inhibitory modulation of phrenic activity by serotonin (5-HT) via non-5-HT2A receptors [Lindsay, A.D. and Feldman, J.L., Modulation of respiratory activity of neonatal rat phrenic motoneurones by serotonin, J. Physiol., 461 (1993) 213-233]. The changes induced by 5-HT and related agents on phrenic root discharges and membrane currents in identified phrenic motoneurons were analysed after blockade of spinal 5-HT2A receptors. Spinal application of 5-HT1B (but not 5-HT1A) receptor agonists depressed the phrenic activity and the effect was prevented by pretreatment with 5-HT1B (but not 5-HT1A, 5-HT2A and 5-HT3) receptor antagonists. Results from phrenic motoneuron whole cell recordings do not reject a presynaptic location of the 5-HT receptors responsible for this depression