Article

Proteolipid protein gene mutation induces altered ventilatory response to hypoxia in the myelin-deficient rat

Department of Pediatrics, Case Western Reserve University and Rainbow Babies and Children's Hospital, Cleveland, Ohio 44106, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 04/2003; 23(6):2265-73.
Source: PubMed

ABSTRACT Pelizaeus Merzbacher disease is an X-linked dysmyelinating disorder of the CNS, resulting from mutations in the proteolipid protein (PLP) gene. An animal model for this disorder, the myelin-deficient (MD) rat, carries a point mutation in the PLP gene and exhibits a phenotype similar to the fatal, connatal disease, including extensive dysmyelination, tremors, ataxia, and death at approximately postnatal day 21 (P21). We postulated that early death might result from disruption of myelinated neural pathways in the caudal brainstem and altered ventilatory response to oxygen deprivation or hypercapnic stimulus. Using barometric plethysmography to measure respiratory function, we found that the MD rat develops lethal hypoxic depression of breathing at P21, but hypercapnic ventilatory response is normal. Histologic examination of the caudal brainstem in the MD rat at this age showed extensive dysmyelination and downregulation of NMDA and to a lesser extent GABA(A) receptors on neurons in the nucleus tractus solitarius, hypoglossal nucleus, and dorsal motor nucleus of the vagus. Unexpectedly, immunoreactive PLP/DM20 was detected in neurons in the caudal brainstem. Not all biosynthetic functions and structural elements were altered in these neurons, because phosphorylated and nonphosphorylated neurofilament and choline acetyltransferase expression were comparable between MD and wild-type rats. These findings suggest that PLP is expressed in neurons in the developing brainstem and that PLP gene mutation can selectively disrupt central processing of afferent neural input from peripheral chemoreceptors, leaving the central chemosensory system for hypercapnia intact.

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    • "However, studies during hypoxia were discontinued following the death of several les rats during the fist minutes of hypoxic exposure caused by prolonged apneas associated with seizure-like activity (see results). The finding of terminal apneas during hypoxia is reminiscent of a previous report in a different rodent model of dysmyelination (Miller et al., 2003). "
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    ABSTRACT: Although respiratory complications significantly contribute to morbidity/mortality in advanced myelin disorders, little is known concerning mechanisms whereby dysmyelination impairs ventilation, or how patients compensate (i.e. plasticity). To establish a model for studies concerning mechanisms of ventilatory impairment/compensation, we tested the hypotheses that respiratory function progressively declines in a model of CNS dysmyelination, the Long Evans shaker rat (les). The observed impairment is associated with abnormal inspiratory neural output. Minimal myelin staining was found throughout the CNS of les rats, including the brainstem and cervical bulbospinal tracts. Ventilation (via whole-body plethysmography) and phrenic motor output were assessed in les and wild-type (WT) rats during baseline, hypoxia (11% O(2)) and hypercapnia (7% CO(2)). Hypercapnic ventilatory responses were similar in young adult les and WT rats (2 months old); in hypoxia, rats exhibited seizure-like activity with sustained apneas. However, 5-6 month old les rats exhibited decreased breathing frequencies, mean inspiratory flow (V(T)/T(I)) and ventilation (V (E)) during baseline and hypercapnia. Although phrenic motor output exhibited normal burst frequency and amplitude in 5-6 month old les rats, intra-burst activity was abnormal. In WT rats, phrenic activity was progressive and augmenting; in les rats, phrenic activity was decrementing with asynchronized, multipeaked activity. Thus, although ventilatory capacity is maintained in young, dysmyelinated rats, ventilatory impairment develops with age, possibly through discoordination in respiratory motor output. This study is the first reporting age-related breathing abnormalities in a rodent dysmyelination model, and provides the foundation for mechanistic studies of respiratory insufficiency and therapeutic interventions.
    Neuroscience 09/2010; 169(3):1105-14. DOI:10.1016/j.neuroscience.2010.06.010 · 3.33 Impact Factor
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    • "Nonetheless, the identification of DM20 in non-myelinating cells suggests an alternative function for the protein in these cells (Campagnoni et al., 1992; Pribyl et al., 1996a, 1996b; Feng et al., 2003; Skoff et al., 2004a). Apart from its expression in mature OLs, the gene encoding PLP is also expressed in OPCs (Gudz et al., 2006), neurons (Bongarzone et al., 1999; Jacobs et al., 2003, 2004; Miller et al., 2003, 2009), embryonic neural precursors (Spassky et al., 1998; Delaunay et al., 2009) and non-neural cells (Campagnoni et al., 1992; Skoff et al., 2004a). The presence of PLP proteins in non-myelinating cells suggests an involvement in other functions unrelated to myelination. "
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    ABSTRACT: It has become clear that the products of several of the earliest identified myelin protein genes perform functions that extend beyond the myelin sheath. Interestingly, these myelin proteins, which comprise proteolipid protein, 2′,3′-cyclic nucleotide 3′-phosphodiesterase and the classic and golli MBPs (myelin basic proteins), play important roles during different stages of oligodendroglial development. These non-myelin-related functions are varied and include roles in the regulation of process outgrowth, migration, RNA transport, oligodendrocyte survival and ion channel modulation. However, despite the wide variety of cellular functions performed by the different myelin genes, the route by which they achieve these many functions seems to converge upon a common mechanism involving Ca2+ regulation, cytoskeletal rearrangements and signal transduction. In the present review, the newly emerging functions of these myelin proteins will be described, and these will then be discussed in the context of their contribution to oligodendroglial development.
    ASN Neuro 01/2010; 2(1). DOI:10.1042/AN20090051 · 4.44 Impact Factor
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    • "The present study and our earlier studies (Miller et al., 2003, 2004) raise the possibility that Plp mutation could directly influence neuronal function in diverse areas of the CNS of these patients. For example, in in vitro models of epilepsy, down-regulation of SK channel mediated afterhyperpolarization was observed to parallel the emergence of epileptiform activity (Fernandez de Sevilla et al., 2006). "
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    ABSTRACT: Proteolipid protein (Plp) gene mutation in rodents causes severe CNS dysmyelination, early death, and lethal hypoxic ventilatory depression (Miller et al., 2004). To determine if Plp mutation alters neuronal function critical for control of breathing, the nucleus tractus solitarii (nTS) of four rodent strains were studied: myelin deficient rats (MD), myelin synthesis deficient (Plp(msd)), and Plp(null) mice, as well as shiverer (Mbp(shi)) mice, a myelin basic protein mutant. Current-voltage relationships were analyzed using whole-cell patch-clamp in 300 microm brainstem slices. Voltage steps were applied, and inward and outward currents quantified. MD, Plp(msd), and Plp(null), but not Mbp(shi) neurons exhibited reduced outward current in nTS at P21. Apamin blockade of SK calcium-dependent currents and iberiotoxin blockade of BK calcium-dependent currents in the P21 MD rat demonstrated reduced outward current due to dysfunction of these channels. These results provide evidence that Plp mutation specifically alters neuronal excitability through calcium-dependent potassium channels in nTS.
    Respiratory Physiology & Neurobiology 10/2009; 169(3):303-14. DOI:10.1016/j.resp.2009.09.013 · 1.97 Impact Factor
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