Postnatal development of brain‐derived neurotrophic factor (BDNF) and tyrosine protein kinase B (TrkB) receptor immunoreactivity in multiple brain stem respiratory‐related nuclei of the rat

Abstract

Previously, we found a transient imbalance between suppressed excitation and enhanced inhibition in the respiratory network of the rat around postnatal days (P) 12–13, a critical period when the hypoxic ventilatory response is at its weakest. The mechanism underlying the imbalance is poorly understood. Brain-derived neurotrophic factor (BDNF) and its tyrosine protein kinase B (TrkB) receptors are known to potentiate glutamatergic and attenuate gamma-aminobutyric acid (GABA)ergic neurotransmission, and BDNF is essential for respiratory development. We hypothesized that the excitation-inhibition imbalance during the critical period stemmed from a reduced expression of BDNF and TrkB at that time within respiratory-related nuclei of the brain stem. An in-depth, semiquantitative immunohistochemical study was undertaken in seven respiratory-related brain stem nuclei and one nonrespiratory nucleus in P0–21 rats. The results indicate that the expressions of BDNF and TrkB: 1) in the pre-Bötzinger complex, nucleus ambiguus, commissural and ventrolateral subnuclei of solitary tract nucleus, and retrotrapezoid nucleus/parafacial respiratory group were significantly reduced at P12, but returned to P11 levels by P14; 2) in the lateral paragigantocellular nucleus and parapyramidal region were increased from P0 to P7, but were strikingly reduced at P10 and plateaued thereafter; and 3) in the nonrespiratory cuneate nucleus showed a gentle plateau throughout the first 3 post-natal weeks, with only a slight decline of BDNF expression after P11. Thus, the significant downregulation of both BDNF and TrkB in respiratory-related nuclei during the critical period may form the basis of, or at least contribute to, the inhibitory-excitatory imbalance within the respiratory network during this time.

Postnatal development of glycine receptor subunits α1, α2, α3, and β immunoreactivity in multiple brain stem respiratory-related nuclear groups of the rat

“…In addition to a switch in dominance from the neonatal GlyRα2 and/or α3 to the mature GlyRα1 (the present study) that signals a more robust inhibition, the transient rise in inhibition during the critical period is further contributed by several factors occurring concurrently: a) a switch in the dominance of expression from NKCC1 to KCC2, enabling either a transition from depolarizing to hyperpolarizing, or a strengthening of the hyperpolarizing potentials mediated by GABA and glycine receptors (Liu and Wong-Riley, 2012); b) a switch in dominance from the neonatal α3 to the mature α1 for the GABA A receptors (Liu and Wong-Riley, 2004, 2006); c) a suppressed expression of multiple serotonergic receptors, serotonin transporter, and serotonin synthesizing enzyme in multiple brain stem respiratory-related nuclear groups (Liu and Wong-Riley, 2008; 2010a,b), which would attenuate the “net stimulatory effect” of serotonin on respiratory output (Lindsay and Feldman, 1993; Hodges and Richerson, 2008); reduced 5-HT 1A R expression would also imply that its disinhibitory effect on respiration via GlyRα3 (Manzke et al, 2010; Shevtsova et al, 2011) would be diminished; and d) a significant reduction in the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor (tyrosine protein kinase B, TrkB) in multiple respiratory-related nuclear groups (Liu and Wong-Riley, 2013) indicates that their normal enhancement of excitation and suppression of inhibition (Wardle and Poo, 2003) would be reduced. These cumulative effects culminate in a transient state of augmented inhibition during the critical period that eventually subsides into a more balanced state of excitation and inhibition.…”

Transient downregulation of BDNF is required for GABAergic maturation in rat primary visual cortex

“…Furthermore, the nature of this relationship may differ between brain areas. For example, a transient reduction in BDNF expression has been observed in the early development of a number of rat respiratory brainstem nuclei (Liu & Wong‐Riley, ). In a recent article, Zhang et al .…”

Morphological Characterization of Respiratory Neurons in the Pre-Bötzinger Complex

“…However, these models still lack a functional-anatomical correlation of the included neurons, the actual synaptic connections between them, as well as the distinctive morphological features of the respiratory neurons in the preBötC. Several of these molecular markers have been indeed located in the preBötC but also in other respiratory-related circuits throughout the brainstem (Gray et al, 1999(Gray et al, , 2001(Gray et al, , 2010Guyenet et al, 2002;Kang et al, 2013;Liu and Wong-Riley, 2013;Stornetta et al 2003;Tan et al, 2012). Several of these molecular markers have been indeed located in the preBötC but also in other respiratory-related circuits throughout the brainstem (Gray et al, 1999(Gray et al, , 2001(Gray et al, , 2010Guyenet et al, 2002;Kang et al, 2013;Liu and Wong-Riley, 2013;Stornetta et al 2003;Tan et al, 2012).…”