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 - PubMed (original) (raw)

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

J T Erickson et al. J Neurosci. 1996.

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.

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Figures

Fig. 1.

Fig. 1.

Photomicrographs of hematoxylin- and eosin-stained sections through the nodose ganglion from (A) wild-type, (B)bdnf_−/−_nt4+/+, (C)bdnf+/+_nt4_−/−, (D)bdnf_−/−_nt4_−/−, and (E) trkb_−/− mice. Compared with the wild-type, ganglion size and cell number were reduced significantly in_bdnf_−/−_nt4+/+and_bdnf+/+_nt4_−/−mice and further reduced in_bdnf_−/−_nt4_−/−and _trkb_−/− animals. Scale bar, 50 μm.

Fig. 2.

Fig. 2.

Photomicrographs of TH-immunostained sections through the petrosal ganglion, taken at the level of the glossopharyngeal nerve (arrow), from (A) wild-type, (B)bdnf+/+_nt4_−/−, (C)bdnf_−/−_nt4+/+, (D)_bdnf_−/−_nt4_−/−, and (E) trkb_−/− mice. Compared with the wild-type, the number of TH+ profiles was reduced significantly in_bdnf_−/−_nt4+/+,_bdnf_−/−_nt4_−/−, and trkb_−/− mice but was unchanged in_bdnf+/+_nt4_−/−animals. Scale bar, 100 μm.

Fig. 3.

Fig. 3.

BDNF and NT4 support survival of DA nodose neurons to the same degree in vitro. Values are means ± SEM of cell counts from three separate experiments with three cultures per condition per experiment. The presence of BDNF and NT4 together does not increase TH+ neuron number, as compared with cultures supplemented with either neurotrophin alone. Moreover, total neuronal survival was similar in the presence of BDNF, NT4, or BDNF plus NT4 (BDNF alone, 3570 ± 268; NT4 alone, 3525 ± 300; BDNF plus NT4, 3628 ± 181 neurons, respectively).

Fig. 4.

Fig. 4.

Plethysmograph records of resting ventilation in normoxia from individual bdnf+/+ and_bdnf_−/− littermates during the first 4 d of postnatal life (P0.5–P4.5). Differences in the pattern of resting ventilation between wild-type and knockout animals were apparent as early as 6–12 hr after birth. Scale bars: vertical, 20 μl; horizontal, 2 sec.

Fig. 5.

Fig. 5.

Ventilatory responses of individual neonatal mice to hyperoxia (A) and hypercapnia (B). Records show periods of quiet breathing without apneas.A, Hyperoxia depresses ventilation in P2.5 wild-type (+/+) mice, primarily via a decrease in _V_T, but had no significant effect on either _V_Tor f in knockout (−/−) animals. B, P3 knockout mice were capable of increasing respiratory output above resting normoxic levels in response to 5% CO2. Scale bars: vertical, 20 μl; horizontal, 2 sec.

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