Cell-specific loss of κ-opioid receptors in oligodendrocytes of the dysmyelinating jimpy mouse
Introduction
Jimpy is an X-linked mutation in the proteolipid protein (PLP) gene that causes a dysmyelinating phenotype in the central nervous system (CNS) [40], [50]. A single nucleotide change inactivates a splice acceptor site, resulting in excision of exon 5 from PLP mRNA [21], [32], [34]. The mutation also causes a frameshift, making the predicted COOH terminus of jimpy PLP completely abnormal. Jimpy is a bona fide model of dominant-negative forms of human Pelizaeus–Merzbacher disease, a rare, inherited, leukodystrophy associated with mutations in, or duplications of, the PLP gene [23], [48]. Jimpy mice produce little CNS myelin, likely due to premature death of oligodendrocytes (OLs) throughout the CNS coincident with active myelination [30]. Arborization, myelin membrane formation, and survival are adversely affected in vivo and in culture. Jimpy mice exhibit tremors by 8–10 days, followed by death at 20–28 days. OLs from jimpy mice show additional abnormalities that appear unrelated to loss of a myelin protein. These include altered pH, Em, [Ca2+]i, metabolic function, cAMP signaling, and proliferation/cell cycle [11], [12], [25], [26], [29], [42]. Many defects occur in situ or in culture long before the cells die, suggesting a direct or indirect contribution to OL death and dysmyelination. We previously showed that jimpy OLs grown in vitro also fail to express κ-opioid receptors (KOP), although most normal OLs express KOP throughout development [28]. The present study examined expression of KOP by jimpy OLs in vivo. Endogenous opioids normally modulate aspects of glial development [15], [16], [20], [28], [36], [38], [44]. Therefore, KOP loss might contribute to abnormalities in OL phenotype and function both in jimpy mice and in human diseases involving PLP mutations.
Section snippets
Methods
Jimpy mice were bred from carrier pairs (B6CBACa Aw–J/A-Plp1jp EdaTa/J) (Jackson Laboratory, Bar Harbor, ME). 16–18 day mutant mice were identified by characteristic tremors. Younger mutants were identified by DdeI restriction analysis after PCR amplification [26]. Mice were anaesthetized by halothane exposure, using procedures to minimize pain outlined in the NIH Guide for Care and Use of Laboratory Animals, then perfused transcardially with 4% Zamboni's fixative. Cerebral hemispheres were
Results and discussion
Tissue from 5 to 8 day jimpy animals contained a seemingly normal complement of OLs, consistent with reports that immature stages of the lineage are phenotypically normal, and that dysmyelination and OL death occur when OLs begin to produce myelin [13], [30]. Even though cell density and morphology appeared normal, both cell counts (Fig. 1) and immunostaining (Fig. 2) showed a substantial reduction in the percentage of APC+ OLs expressing KOP in 5–8 day corpus callosum. While 67.4% of OLs in
Acknowledgements
We acknowledge generous NIH support: R01 DA15097 and P01 DA19398.
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