PDGF-β Receptor Expression in the Dorsocaudal Brainstem Parallels Hypoxic Ventilatory Depression in the Developing Rat

Abstract

The temporal trajectory of platelet-derived growth factor (PDGF)-␤ receptor activation within the dorsocaudal brainstem parallels that of the mild hypoxic ventilatory depression (HVD) seen in adult rats. We hypothesized that enhanced PDGF-␤ receptor activity may account for the particularly prominent HVD of developing mammals. To study this issue, 2-, 5-, 10-, and 20-d-old rats underwent hypoxic challenges (10% O 2 for 30 min) after pretreatment with either vehicle (Veh) or the selective PDGF-␤ receptor antagonist CGP57148B (intraperitoneal 100 mg/kg). The developmental characteristics and magnitude of the peak hypoxic ventilatory response (HVR) were not modified by the PDGF-␤ receptor blocker. However, HVD was markedly attenuated by CGP57148B, and such effect, although still present, gradually abated with increasing postnatal age [p Ͻ 0.001, analysis of variance (ANOVA)]. Hypercapnic ventilatory responses were not affected by CGP57148B. The expression of PDGF-␤ receptor in the dorsocaudal brainstem was assessed by immunoblotting and confirmed progressively decreasing expression with maturation. We conclude that PDGF-␤ receptor activation during hypoxia is an important contributor to HVD at all postnatal ages but more particularly in the immature rat. The acute ventilatory response to hypoxia in adult mammalian species is biphasic. In the rat, after the initial ventilatory increase (which is primarily mediated by integration of peripheral chemoreceptor afferent input) there is a subsequent mild decrease in ventilation to levels that are lower than the peakearly ventilatory increase, although they exceed those during normoxia(1). In most neonatal mammals, however, this second phase of the HVR, also named HVD, is particularly prominent, and ventilation is usually reduced below normoxic levels (2). The mechanisms underlying HVD are complex and probably involve interaction of multiple neural pathways. In addition to decreases in oxygen consumption (3), GABA and adenosine release during hypoxia will further add to HVD, as will the relative paucity of nNOS expression within several brainstem nuclei mediating HVR (4 -7). Furthermore, several other mechanisms involving opioid receptors and local release of various neuroactive peptides have also been implicated in HVD (reviewed in ref. 8).In a recent study, we found that activation of PDGF-␤ receptors within the NTS modulated HVD in the adult freely behaving rat, as well as in the adult mouse. Indeed, pharmacological inhibition or diminished expression of PDGF-␤ re-

Cognitive and Socio-Emotional Deficits in Platelet-Derived Growth Factor Receptor-β Gene Knockout Mice

“…Since previous reports have shown that PDGFR-β is expressed in the cortex, hippocampus, amygdala, and brainstem [5], [3], [65], PDGFR-β deletion may result in a decrease in the long-term synaptic plasticity of various brain regions. Consistent with this concept, recent studies have reported that PDGF-B is important for long-term potentiation (LTP) in the hippocampus of mice and regulates expression of Arc/Arg3.1 , a gene that has been implicated in synaptic plasticity and LTP [66], and that LTP is disturbed in the hippocampus of the PDGFR-β KO mice [67].…”

Effect of prenatal nicotine exposure on biphasic hypoxic ventilatory response and protein kinase C expression in caudal brain stem of developing rats

“…In fact, hypoxia-induced activation of the PDGF-␤ receptor in the CB is temporally associated with activation of an antiapoptotic mechanism via phosphatidylinositol 3-kinase-dependent phosphorylation of both Akt and BAD pathway (38). In addition, activation of PDGF-␤ receptor is an important contributor to hypoxic ventilatory roll-off at all postnatal ages but more critical in developing animals (45). Because prenatal nicotine exposure is associated with modulation of hypoxic ventilatory roll-off, it could lead to perturbation of this important protective mechanism, which may lead to decreased hypoxic tolerance of brain stem neurons.…”

Loop Gain and Sleep Disordered Breathing

“…Mechanisms proposed include central accumulation and/or release of inhibitory neurotransmitters on respiratory neurons [40]. There is an identified role for protein factors, like PDGF and its receptors, in this response [41][42][43].…”