Altered Respiratory Activity and Respiratory Regulations in Adult Monoamine Oxidase A-Deficient Mice

Abstract

The abnormal metabolism of serotonin during the perinatal period alters respiratory network maturation at birth as revealed by comparing the monoamine oxidase A-deficient transgenic (Tg8) with the control (C3H) mice (Bou-Flores et al., 2000). To know whether these alterations occur only transiently or induce persistent respiratory dysfunction during adulthood, we studied the respiratory activity and regulations in adult C3H and Tg8 mice. First, plethysmographic and pneumotachographic analyses of breathing patterns revealed weaker tidal volumes and shorter inspiratory durations in Tg8 than in C3H mice. Second, electrophysiological studies showed that the firing activity of inspiratory medullary neurons and phrenic motoneurons is higher in Tg8 mice and that of the intercostal motoneurons in C3H mice. Third, histological studies indicated abnormally large cell bodies of Tg8 intercostal but not phrenic motoneurons. Finally, respiratory responses to hypoxia and lung inflation are weaker in Tg8 than in C3H mice. DL-p-chlorophenyl-alanine treatments applied to Tg8 mice depress the high serotonin level present during adulthood; the treated mice recover normal respiratory responses to both hypoxia and lung inflation, but their breathing parameters are not significantly affected. Therefore in Tg8 mice the high serotonin level occurring during the perinatal period alters respiratory network maturation and produces a permanent respiratory dysfunction, whereas the high serotonin level present in adults alters the respiratory regulatory processes. In conclusion, the metabolism of serotonin plays a crucial role in the maturation of the respiratory network and in both the respiratory activity and the respiratory regulations.

Phox2a Gene, A6 Neurons, and Noradrenaline Are Essential for Development of Normal Respiratory Rhythm in Mice

“…As reported previously (Burnet et al, 2001;Gaytan et al, 2002), the challenge virus standard (CVS) rabies virus is amplified across the synapses and can be used to transynaptically label the respiratory network. After cold anesthesia of three P1 neonates, 1 l of CVS rabies virus solution (2.5 ϫ 10 7 PFU/ml) was injected via a 10 l Hamilton syringe inserted into the left part of the diaphragm.…”

“…The breathing movements of surgically delivered fetuses were recorded as described previously (Burnet et al, 2001;Blanchi et al, 2003;Viemari et al, 2003), using the whole-body plethysmography technique in 25 ml thermostated chambers equipped with a differential pressure transducer connected to a sine-wave carrier demodulator (Validyne CD15, Northbridge, CA). Mouth temperature was monitored with a miniature thermistor nyloncoated probe (YSI 555; Cole-Parmer, Vernon Hills, IL).…”

“…Finally, we examined whether there is anatomical support for this modulation, i.e., if any synaptic relationships exist between pontine A6 neurons and the medullary respiratory network. We transynaptically labeled the pontomedullary respiratory network by administering diaphragmatic injections of rabies virus, as described previously in adults (Burnet et al, 2001;Gaytan et al, 2002). Rabies virus was injected into the diaphragm of three P1 neonatal mice, and the pups were killed 48 hr later.…”

“…The very high endogenous serotonin levels occurring in monoamine oxydase A-deficient mice (Cases et al, 1995;Lajard et al, 1999) affect respiratory network maturation, but the resulting alterations are not drastic and do not affect pups' survival (Bou-Flores et al, 2000;Burnet et al, 2001), whereas the lack of A6 neurons in Phox2a mutants significantly alters the respiratory rhythmogenesis at birth and is lethal. The differentiation of NA central neurons during CNS development is controlled by several homeobox genes such as the two closely related members of the Phox/aristaless family of paired-class homeobox genes, the Phox2a and Phox2b transcription factors, and the homeodomain protein Rnx/Tlx3 and bHLH transcription factor Mash1 (Tiveron et al, 1996;Pattyn et al, 1997Pattyn et al, , 1999Pattyn et al, , 2000Hirsch et al, 1998;Lo et al, 1998;Qian et al, 2001Qian et al, , 2002.…”

Invited Review: Neuroplasticity in respiratory motor control

“…An altered capacity for neuromodulation resulting from changes in any of these factors is both a form of plasticity and a form of metamodulation. Notable examples of plasticity via metamodulation include serotonin-dependent plasticity in the social status of crayfish (244), altered serotonin transport protein function (174), altered serotonin degradation (25,28), and alterations in serotonin-dependent respiratory plasticity following chronic spinal sensory denervation (63,106,120).…”