Brain-derived neurotrophic factor enhances fetal respiratory rhythm frequency in the mouse preBotzinger complex in vitro

Laboratoire de Neurobiologie Génétique et Intégrative, Institut Alfred Fessard, Centre National de la Recherche Scientifique, 91198 Gif sur Yvette, France.
European Journal of Neuroscience (Impact Factor: 3.18). 09/2008; 28(3):510-20. DOI: 10.1111/j.1460-9568.2008.06345.x
Source: PubMed


Brain-derived neurotrophic factor (BDNF) is required during the prenatal period for normal development of the respiratory central command; however, the underlying mechanisms remain unknown. To approach this issue, the present study examined BDNF regulation of fetal respiratory rhythm generation in the preBötzinger complex (preBötC) of the mouse, using transverse brainstem slices obtained from prenatal day 16.5 animals. BDNF application (100 ng/mL, 15 min) increased the frequency of rhythmic population activity in the preBötC by 43%. This effect was not observed when preparations were exposed to nerve growth factor (100 ng/mL, 30 min) or pretreated with the tyrosine kinase inhibitor K252a (1 h, 200 nm), suggesting that BDNF regulation of preBötC activity requires activation of its cognate tyrosine receptor kinase, TrkB. Consistent with this finding, single-cell reverse transcription-polymerase chain reaction experiments showed that one third of the rhythmically active preBötC neurons analysed expressed TrkB mRNA. Moreover, 20% expressed BDNF mRNA, suggesting that the preBötC is both a target and a source of BDNF. At the network level, BDNF augmented activity of preBötC glutamatergic neurons and potentiated glutamatergic synaptic drives in respiratory neurons by 34%. At the cellular level, BDNF increased the activity frequency of endogenously bursting neurons by 53.3% but had no effect on basal membrane properties of respiratory follower neurons, including the Ih current. Our data indicate that BDNF signalling through TrkB can acutely modulate fetal respiratory rhythm in association with increased glutamatergic drive and bursting activity in the preBötC.

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Available from: Julien Bouvier, Oct 05, 2015
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    • "heterogeneous group of glutamatertgic neurons expressing, constantly or transiently, DbX1 (Bouvier et al., 2010; Gray et al., 2010; Picardo et al., 2013), Robo3 (Bouvier et al., 2010), NK1R (Gray et al., 1999, 2010; Guyenet et al., 2002), and somatostatin (Gray et al., 1999, 2010; Llona and Eugenín, 2005; Stornetta et al., 2003), constitute an essential component of the preBötC. Several attempts have been made to relate the presence of such molecular markers with morphological and/or electrophysiological features of the preBötC neurons (Bouvier et al., 2008, 2010; Hayes and Del Negro, 2007; Koizumi et al., 2008, 2013; Morgado-Valle et al., 2010; Pagliardini et al., 2005; Picardo et al., 2013). Here, to obtain more information regarding the functional–anatomical characteristics of the neuronal elements that constitute the respiratory network contained in the preBötC, we have characterized the morphology of cells identified as respiratory neurons. "
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    ABSTRACT: Although the pre-Bötzinger complex (preBötC) was defined as the inspiratory rhythm generator long ago, the functional-anatomical characterization of its neuronal components is still being achieved. Recent advances have identified the expression of molecular markers in the preBötC neurons that, however, are not exclusive to specific respiratory neuron subtypes and have not always been related to specific cell morphologies. Here, we evaluated the morphology and the axonal projections of electrophysiologically defined respiratory neurons in the preBötC using whole-cell recordings and intracellular biocytin labeling. We found that respiratory pacemaker neurons are larger than expiratory neurons and that inspiratory neurons are smaller than pacemaker and expiratory neurons. Other morphological features such as somata shapes or dendritic branching patterns were not found to be significantly different among the preBötC neurons sampled. We also found that both pacemaker and inspiratory nonpacemaker neurons, but not expiratory neurons, show extensive axonal projections to the contralateral preBötC and show signs of electrical coupling. Overall, our data suggest that there are morphological differences between subtypes of preBötC respiratory neurons. It will be important to take such differences in consideration since morphological differences would influence synaptic responses and action potential propagation.
    Progress in brain research 04/2014; 209:39-56. DOI:10.1016/B978-0-444-63274-6.00003-5 · 2.83 Impact Factor
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    • "We demonstrated that activation of TRPC3 ⁄ 7 by synaptically released SubP signaling improves the respiratory rhythm regularity. These data do not exclude the possible contribution of other neuromodulators that can activate TRPC channels, such as brain-derived neurotrophic factor (BDNF) (Bouvier et al., 2008). Dysregulation of BDNF signaling has been hypothesized to underlie the functional and structural consequences of MeCP2 mutations in Rett syndrome (Amaral et al., 2007). "
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    ABSTRACT: Neuromodulators, such as substance P (SubP), play an important role in modulating many rhythmic activities driven by central pattern generators (e.g. locomotion, respiration). However, the mechanism by which SubP enhances breathing regularity has not been determined. Here, we used mouse brainstem slices containing the pre-Bötzinger complex to demonstrate, for the first time, that SubP activates transient receptor protein canonical (TRPC) channels to enhance respiratory rhythm regularity. Moreover, SubP enhancement of network regularity is accomplished via selective enhancement of ICAN (inward non-specific cation current)-dependent intrinsic bursting properties. In contrast to INaP (persistent sodium current)-dependent pacemakers, ICAN-dependent pacemaker bursting activity is TRPC-dependent. Western Blots reveal TRPC3 and TRPC7 channels are expressed in rhythmically active ventral respiratory group island preparations. Taken together, these data suggest that SubP-mediated activation of TRPC3/7 channels underlies rhythmic ICAN-dependent pacemaker activity and enhances the regularity of respiratory rhythm activity.
    European Journal of Neuroscience 03/2010; 31(7):1219-32. DOI:10.1111/j.1460-9568.2010.07156.x · 3.18 Impact Factor
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    • "Up to now the molecular effects of BDNF on the development of neuronal circuitry in RTT mice have not been identified. MeCP2 null mice show distinct signs of breathing disturbances (Viemari et al. 2005; Stettner et al. 2007) that can be related to BDNF, with trkB receptors that are important in the generation of the respiratory rhythm (Bouvier et al. 2008). The actions of Ca 2+ as second messenger are versatile (Berridge et al. 2000) and Ca 2+ plays an important role in generating rhythmic activity in the respiratory network (Mironov, 2008, 2009). "
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    ABSTRACT: Rett syndrome caused by MeCP2 mutations is a devastating neurodevelopmental disorder accompanied by severe breathing irregularities. Using transduction of organotypic slices from model MeCP2-/y mice with neuron-specific calcium sensor protein D3cpv, we examined the slow calcium buffering in neurons in pre-Bötzinger complex (preBötC), a component of the complex respiratory network. Examination of wild-type (WT) and MeCP2 null mice showed clear differences in the spatial organisations of neurons in preBötC and also in the disturbances in calcium homeostasis in mutant mice during early postnatal development. Deregulated calcium buffering in MeCP2-/y neurons was indicated by increased amplitude and kinetics of depolarisation-induced calcium transients. Both effects were related to an insufficient calcium uptake into the endoplasmic reticulum that was restored after pretreatment with brain-derived neurotrophic factor (BNDF). Conversely, the inhibition of BDNF signalling in WT neurons produced disturbances similar to those observed in MeCP2-/y mice. Brief hypoxia and calcium release from internal stores induced global calcium increases, after which the processes of many MeCP2-/y neurons were retracted, an effect that was also corrected by pretreatment with BDNF. The data obtained point to a tight connection between calcium homeostasis and long-term changes in neuronal connectivity. We therefore propose that calcium-dependent retraction of neurites in preBötC neurons can cause remodelling of the neuronal network during development and set up the conditions for appearance of breathing irregularities in Rett model mice.
    The Journal of Physiology 05/2009; 587(Pt 11):2473-85. DOI:10.1113/jphysiol.2009.169805 · 5.04 Impact Factor
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