Invited review: Intermittent hypoxia and respiratory plasticity.

Intermittent hypoxia elicits long-term facilitation (LTF), a persistent augmentation (hours) of respiratory motor output. Considerable recent progress has been made toward an understanding of the mechanisms and manifestations of this potentially important model of respiratory plasticity. LTF is elicited by intermittent but not sustained hypoxia, indicating profound pattern sensitivity in its underlying mechanism. During intermittent hypoxia, episodic spinal serotonin receptor activation initiates cell signaling events, increasing spinal protein synthesis. One associated protein is brain-derived neurotrophic factor, a neurotrophin implicated in several forms of synaptic plasticity. Our working hypothesis is that increased brain-derived neurotrophic factor enhances glutamatergic synaptic currents in phrenic motoneurons, increasing their responsiveness to bulbospinal inspiratory inputs. LTF is heterogeneous among respiratory outputs, differs among experimental preparations, and is influenced by age, gender, and genetics. Furthermore, LTF is enhanced following chronic intermittent hypoxia, indicating a degree of metaplasticity. Although the physiological relevance of LTF remains unclear, it may reflect a general mechanism whereby intermittent serotonin receptor activation elicits respiratory plasticity, adapting system performance to the ever-changing requirements of life.     

The function of the respiratory supercomplexes: The plasticity model

Mitochondria are important organelles not only as efficient ATP generators but also in controlling and regulating many cellular processes. Mitochondria are dynamic compartments that rearrange under stress response and changes in food availability or oxygen concentrations. The mitochondrial electron transport chain parallels these rearrangements to achieve an optimum performance and therefore requires a plastic organization within the inner mitochondrial membrane. This consists in a balanced distribution between free respiratory complexes and supercomplexes. The mechanisms by which the distribution and organization of supercomplexes can be adjusted to the needs of the cells are still poorly understood. The aim of this review is to focus on the functional role of the respiratory supercomplexes and its relevance in physiology. This article is part of a Special Issue entitled: Dynamic and ultrastructure of bioenergetic membranes and their components.     

Invited review: Neural network plasticity in respiratory control.

Respiratory network plasticity is a modification in respiratory control that persists longer than the stimuli that evoke it or that changes the behavior produced by the network. Different durations and patterns of hypoxia can induce different types of respiratory memories. Lateral pontine neurons are required for decreases in respiratory frequency that follow brief hypoxia. Changes in synchrony and firing rates of ventrolateral and midline medullary neurons may contribute to the long-term facilitation of breathing after brief intermittent hypoxia. Long-term changes in central respiratory motor control may occur after spinal cord injury, and the brain stem network implicated in the production of the respiratory rhythm could be reconfigured to produce the cough motor pattern. Preliminary analysis suggests that elements of brain stem respiratory neural networks respond differently to hypoxia and hypercapnia and interact with areas involved in cardiovascular control. Plasticity or alterations in these networks may contribute to the chronic upregulation of sympathetic nerve activity and hypertension in sleep apnea syndrome and may also be involved in sudden infant death syndrome.     

Aging and respiratory muscle metabolic plasticity: effects of endurance training.

We examined the oxidative and antioxidant enzyme activities in respiratory and locomotor muscles in response to endurance training in young and aging rats. Young adult (4-mo-old) and old (24-mo-old) female Fischer 344 rats were divided into four groups: 1) young trained (n = 12), 2) young untrained (n = 12), 3) old trained (n = 10), and 4) old untrained (n = 6). Both young and old endurance-trained animals performed the same training protocol during 10 wk of continuous treadmill exercise (60 min/day, 5 days/wk). Compared with young untrained animals, the young trained group had significantly elevated (P less than 0.05) activities of 3-hydroxyacyl-CoA dehydrogenase (HADH), glutathione peroxidase (GPX), and citrate synthase (CS) in both the costal diaphragm and the plantaris muscle. In contrast, training had no influence (P greater than 0.05) on the activity of lactate dehydrogenase within the costal diaphragm in young animals. In the aging animals, training did not alter (P greater than 0.05) activities of CS, HADH, GPX, or lactate dehydrogenase in the costal diaphragm but significantly (P less than 0.05) increased CS, HADH, and GPX activities in the plantaris muscle. Furthermore, training resulted in higher activities of CS and HADH in the intercostal muscles in the old trained than in the old untrained animals. Finally, activities of CS, HADH, and GPX were significantly (P less than 0.05) lower in the plantaris in the old untrained than in the young untrained animals; however, CS, HADH, and GPX activities were greater (P less than 0.05) in the costal diaphragm in the old sedentary than in the young untrained animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Invited review: Mechanisms underlying motor unit plasticity in the respiratory system.

Neuromotor control of skeletal muscles, including respiratory muscles, is ultimately dependent on the function of the motor unit (comprising an individual motoneuron and the muscle fibers it innervates). Considerable diversity exists across diaphragm motor units, yet remarkable homogeneity is present (and maintained) within motor units. In recent years, the mechanisms underlying the development and adaptability of respiratory motor units have received great attention, leading to significant advances in our understanding of diaphragm motor unit plasticity. For example, following imposed inactivity of the diaphragm muscle, there are changes at phrenic motoneurons, neuromuscular junctions, and muscle fibers that tend to restore the ability of the diaphragm to sustain ventilation. The role of activity, neurotrophins, and other growth factors in modulating this adaptability is discussed.     

Neonatal caffeine induces sex-specific developmental plasticity of the hypoxic respiratory chemoreflex in adult rats

Caffeine is widely used to treat apneas of prematurity during the neonatal period; however, the potential consequences of administering a neonatal caffeine treatment (NCT) during a critical period for respiratory control development are unknown. The present study therefore determined whether NCT in rats alters the hypoxic respiratory chemoreflex measured at adulthood. Newborn rats received either caffeine (15 mg/kg) or water (control) each day from postnatal day 3 to 12. The ventilatory response to a hypoxic challenge (inspired O(2) fraction = 0.12) was first evaluated in awake adult female and male rats using whole body plethysmography. Results showed that NCT increased the initial phase of the breathing frequency response to hypoxia in males only. This result was confirmed in anesthetized and artificially ventilated adult male rats where NCT also increased the phrenic burst frequency response to hypoxia. RT-PCR assessment of mRNA encoding for adenosine A(1A) and A(2A) receptors, dopamine D(2) receptors, and tyrosine hydroxylase in the rat carotid bodies showed that NCT enhanced mRNA expression levels of adenosine A(2A), dopamine D(2) receptors, and tyrosine hydroxylase of males but not females. Subsequent experiments on awake male rats showed that injection of the adenosine A(2A) receptor antagonist ZM2413855 (1 mg/kg ip) before ventilatory measurements abolished, in NCT rats, the enhanced respiratory frequency response observed during the early phase of hypoxia. We propose that NCT elicits a sex-specific increase in the hypoxic respiratory chemoreflex, which is related, at least partially, to an enhancement in adenosine A(2A) receptors in the rat carotid body.     

Reactive oxygen species in the plasticity of respiratory behavior elicited by chronic intermittent hypoxia.

Long-term facilitation (LTF) of breathing elicited by episodic hypoxia (EH) is an extensively studied example of plasticity of respiratory motor behavior. Previous studies employed the paradigm of EH wherein each episode of hypoxia was 5 min. This paradigm is rarely encountered in nature. Brief episodes of hypoxia are encountered frequently with recurrent apneas, wherein hypoxic episodes last a few seconds only. Recent studies suggest that chronic intermittent hypoxia (CIH) represents a form of oxidative stress involving reactive O(2) species. The objectives of the present study were to determine 1) whether acute, repeated, brief EH (15 s) elicit LTF in breathing and 2) whether prior conditioning with CIH modulates acute EH-induced LTF of breathing, and if so whether reactive O(2) species are involved. Experiments were performed on anesthetized, vagotomized, paralyzed, and mechanically ventilated rats, and efferent phrenic nerve activity was monitored as an index of respiratory motor output. In control animals, acute EH (15-s hypoxia; 10 episodes; n = 9) increased minute neural respiration, which persisted during 60 min of the posthypoxic period, suggesting LTF of breathing. EH-induced LTF of respiration was markedly augmented in CIH-conditioned animals (15-s hypoxia, 9 episodes/h, 8 h/day for 10 days; n = 9). By contrast, conditioning with a comparable, cumulative duration of sustained hypoxia (4-h hypoxia; n = 8) did not augment LTF elicited by acute EH. Systemic administration of manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (5 mg. kg(-1). day(-1) for 10 days), a potent scavenger of O(2)(-)*, prevented CIH-induced potentiation of LTF (n = 9). These results demonstrate that 1) acute, brief EH elicits LTF in respiratory motor output; 2) prior conditioning with CIH, but not with comparable, cumulative duration of sustained hypoxia, augments LTF elicited by acute EH; and 3) O(2)(-)* radical scavenger prevents CIH-induced potentiation of LTF of respiration.     

Proteasome plasticity

The 26S proteasome is responsible for regulated proteolysis of most intracellular proteins yet the focus of intense regulatory action itself. Proteasome abundance is responsive to cell needs or stress conditions, and dynamically localized to concentrations of substrates. Proteasomes are continually assembled and disassembled, and their subunits subject to a variety of posttranslational modifications. Furthermore, as robust and multi-tasking as this complex is, it does not function alone. A spattering of closely associating proteins enhances complex stability, fine-tunes activity, assists in substrate-binding, recycling of ubiquitin, and more. HEAT repeat caps activate proteasomes, yet share remarkable features with nuclear importins. Fascinating cross talk even occurs with ribosomes through common maturation factors. The dynamics of proteasome configurations and how they relate to diverse activities is the topic of this review.     

Thrombin plasticity

Thrombin is the final protease generated in the blood coagulation cascade. It has multiple substrates and cofactors, and serves both pro- and anti-coagulant functions. How thrombin activity is directed throughout the evolution of a clot and the role of conformational change in determining thrombin specificity are issues that lie at the heart of the haemostatic balance. Over the last 20 years there have been a great number of studies supporting the idea that thrombin is an allosteric enzyme that can exist in two conformations differing in activity and specificity. However, recent work has shown that thrombin in its unliganded state is inherently flexible in regions that are important for activity. The effect of flexibility on activity is discussed in this review in context of the zymogen-to-protease conformational transition. Understanding thrombin function in terms of 'plasticity' provides a new conceptual framework for understanding regulation of enzyme activity in general. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.     

Spinal-cord plasticity

Plasticity is one of the most extensively studied aspects in neuroscience. Interest in it has primarily been related to its proposed role in learning and memory and its relevance to adaptive changes following injury. Plasticity can be evoked by changes in molecular, cellular, and synaptic properties, either as a result of activity-dependent effects, or by relatively slow-acting neuromodulatory transmitters. In addition, it is increasingly recognized that the plasticity evoked by these individual effects can be altered by previous inputs and is thus itself plastic. Here, I will review studies in the lamprey spinal cord that have examined individual and interactive activity-dependent and neuromodulator-mediated plasticity. The results show that activity-dependent and neuromodulator-mediated plasticity evoke neuron-and synapse-specific effects at different levels in the spinal cord, and that interactions within and between these effects can evoke dynamic changes in cellular, synaptic, and network plasticity.     

Thrombin plasticity

Thrombin is the final protease generated in the blood coagulation cascade. It has multiple substrates and cofactors, and serves both pro- and anti-coagulant functions. How thrombin activity is directed throughout the evolution of a clot and the role of conformational change in determining thrombin specificity are issues that lie at the heart of the haemostatic balance. Over the last 20 years there have been a great number of studies supporting the idea that thrombin is an allosteric enzyme that can exist in two conformations differing in activity and specificity. However, recent work has shown that thrombin in its unliganded state is inherently flexible in regions that are important for activity. The effect of flexibility on activity is discussed in this review in context of the zymogen-to-protease conformational transition. Understanding thrombin function in terms of ‘plasticity’ provides a new conceptual framework for understanding regulation of enzyme activity in general. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.     

The crossed phrenic phenomenon: a model for plasticity in the respiratory pathways following spinal cord injury.

Hemisection of the cervical spinal cord rostral to the level of the phrenic nucleus interrupts descending bulbospinal respiratory pathways, which results in a paralysis of the ipsilateral hemidiaphragm. In several mammalian species, functional recovery of the paretic hemidiaphragm can be achieved by transecting the contralateral phrenic nerve. The recovery of the paralyzed hemidiaphragm has been termed the "crossed phrenic phenomenon." The physiological basis for the crossed phrenic phenomenon is as follows: asphyxia induced by spinal hemisection and contralateral phrenicotomy increases central respiratory drive, which activates a latent crossed respiratory pathway. The uninjured, initially latent pathway mediates the hemidiaphragm recovery by descending into the spinal cord contralateral to the hemisection and then crossing the midline of the spinal cord before terminating on phrenic motoneurons ipsilateral and caudal to the hemisection. The purpose of this study is to review work conducted on the crossed phrenic phenomenon and to review closely related studies focusing particularly on the plasticity associated with the response. Because the review deals with recovery of respiratory muscles paralyzed by spinal cord injury, the clinical relevance of the reviewed studies is highlighted.     

Dendritic structural plasticity

Dendrites represent the compartment of neurons primarily devoted to collecting and computating input. Far from being static structures, dendrites are highly dynamic during development and appear to be capable of plastic changes during the adult life of animals. During development, it is a combination of intrinsic programs and external signals that shapes dendrite morphology; input activity is a conserved extrinsic factor involved in this process. In adult life, dendrites respond with more modest modifications of their structure to various types of extrinsic information, including alterations of input activity. Here, the author reviews classical and recent evidence of dendrite plasticity in invertebrates and vertebrates and current progress in the understanding of the molecular mechanisms that underlie this plasticity. Importantly, some fundamental questions such as the functional role of dendrite remodeling and the causal link between structural modifications of neurons and plastic processes, including learning, are still open.     

Genome plasticity inPlasmodium

Extensive genome plasticity inPlasmodium involves frequent loss of dispensable functions under non-selective conditions, polymorphisms in subtelomeric repetitive regions, as well as rapid and apparently concerted variation in the intra-genic repetitive arrays that are typical of plasmodial antigen genes. As an example of the latter type of variation, the region of the merozoite surface antigen gene MSA-1 ofPlasmodium falciparum, which encodes a tri-peptide repeat, is analysed in detail. The example illustrates how evasion of the immune defenses of the vertebrate host can be achieved through repeat homogenization mechanisms, acting at the DNA level, and leading to rapid fixation of variant epitopes. The remarkable ability of Plasmodia to utilize mechanisms which operate on its own nuclear DNA in the course of mitotic multiplication is discussed against the need of life cycle closure as a haploid unicellular. The possibility is suggested that active genomic diversification in a (clonal) multicellular population evolved as an adaptive tool.     

Short-term presynaptic plasticity

Different types of synapses are specialized to interpret spike trains in their own way by virtue of the complement of short-term synaptic plasticity mechanisms they possess. Numerous types of short-term, use-dependent synaptic plasticity regulate neurotransmitter release. Short-term depression is prominent after a single conditioning stimulus and recovers in seconds. Sustained presynaptic activation can result in more profound depression that recovers more slowly. An enhancement of release known as facilitation is prominent after single conditioning stimuli and lasts for hundreds of milliseconds. Finally, tetanic activation can enhance synaptic strength for tens of seconds to minutes through processes known as augmentation and posttetantic potentiation. Progress in clarifying the properties, mechanisms, and functional roles of these forms of short-term plasticity is reviewed here.