Mice Lacking Brain-Derived Neurotrophic Factor Exhibit Visceral Sensory Neuron Losses Distinct from Mice Lacking NT4 and Display a Severe Developmental Deficit in Control of Breathing

Abstract

The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT4) act via the TrkB receptor and support survival of primary somatic and visceral sensory neurons. The major visceral sensory population, the nodose-petrosal ganglion complex (NPG), requires BDNF and NT4 for survival of a full complement of neurons, providing a unique opportunity to compare gene dosage effects between the two TrkB ligands and to explore the possibility that one ligand can compensate for loss of the other. Analysis of newborn transgenic mice lacking BDNF or NT4, or BDNF and NT4, revealed that survival of many NPG afferents is proportional to the number of functional BDNF alleles, whereas only one functional NT4 allele is required to support survival of all NT4-dependent neurons. In addition, subpopulation analysis revealed that BDNF and NT4 can compensate for the loss of the other to support a subset of dopaminergic ganglion cells. Together, these data demonstrate that the pattern of neuronal dependencies on BDNF and NT4 in vivo is far more heterogeneous than predicted from previous studies in culture. Moreover, BDNF knockout animals lack a subset of afferents involved in ventilatory control and exhibit severe respiratory abnormalities characterized by depressed and irregular breathing and reduced chemosensory drive. BDNF is therefore required for expression of normal respiratory behavior in newborn animals.

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

“…There is little information regarding the in vivo respiration of the adult mouse (Tankersley et al, 1997(Tankersley et al, , 1999. In addition, the availability of transgenic mice that present interesting mutations affecting the maturation and activity of respiratory network components (Erickson et al, 1996;Jacquin et al, 1996;Bou-Flores et al, 2000) is useful for analyzing the activity and regulations of respiration.…”

“…The ventilatory responses to hypoxia were studied by the whole-body plethysmography technique, as modified by Bartlett and Tenney (1970) and used repeatedly for studying breathing patterns in mice (Erickson et al, 1996;Jacquin et al, 1996;Tankersley et al, 1997Tankersley et al, , 1999. The animal chamber (200 ml), equipped with a temperature sensor (Checktemp 1, Hanna Instruments, Lingolsheim, France), was connected to a reference chamber of identical volume.…”

Developmental basis of the rostro-caudal organization of the brainstem respiratory rhythm generator

“…Respiratory frequency, neonatal apnoeas and survival were normal. Interestingly, the reverse phenotype (a small tidal volume) has been reported after the decrease (instead of increase) in the peripheral chemoreceptor afferent population by the invalidation of the BDNF (Erickson et al 1996). Diamonds, WT; triangles, Phox2a þ/2 .…”

“…This phenotype, accompanied by an unaltered frequency, is evident at birth and persists afterwards (it was followed until post-natal day 10). Morphological analysis of Phox2a þ/2 animals reveals no anomaly in the pons (parabrachial medial and Kö lliker -Fuse nuclei, pediculo-pontine tegmentum, superior cerebellar peduncles) or in the locus coeruleus region, but highlighted an increase in the number of cells expressing the catecholamine-synthesizing enzyme-tyrosine hydroxylase, a marker of peripheral chemoreceptor afferent neurons (Katz & Black 1986;Erickson et al 1996), in the petrosal sensory ganglion (figure 4a). These data indicate that Phox2a plays a critical role in the ontogeny of the reflex control of inspiration and that abnormality may independently affect rhythm generators and pontine/sensory inspiratory controllers as well as their peripheral reflex control.…”

Neural control of breathing: insights from genetic mouse models

“…BDNF is active until adulthood, particularly on the serotonergic spinal plasticity of breathing caused by intermittent hypoxia. Null mutant newborn mice lacking BDNF had a low respiratory rate and numerous apneas (29). Discharge frequency recorded in brain stem-spinal cord preparations from BDNF mutant newborn mice was more severely decreased in homozygous than in heterozygous animals (3).…”