Protracted social isolation of adult mice induced behavioral, transcriptional and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC) and impaired adult myelination. Social re-integration was sufficient to normalize behavioral and transcriptional changes. Short periods of isolation affected chromatin and myelin, but did not induce behavioral changes. Thus, myelinating oligodendrocytes in the adult PFC respond to social interaction with chromatin changes, suggesting that myelination acts as a form of adult plasticity.
The vertebrate nervous system is characterized by ensheathment of axons with myelin, a multilamellar membrane greatly enriched in the galactolipid galactocerebroside (GalC) and its sulfated derivative sulfatide. We have generated mice lacking the enzyme UDP-galactose:ceramide galactosyltransferase (CGT), which is required for GalC synthesis. CGT-deficient mice do not synthesize GalC or sulfatide but surprisingly form myelin containing glucocerebroside, a lipid not previously identified in myelin. Microscopic and morphometric analyses revealed myelin of normal ultrastructural appearance, except for slightly thinner sheaths in the ventral region of the spinal cord. Nevertheless, these mice exhibit severe generalized tremoring and mild ataxia, and electrophysiological analysis showed conduction deficits consistent with reduced insulative capacity of the myelin sheath. Moreover, with age, CGT-deficient mice develop progressive hindlimb paralysis and extensive vacuolation of the ventral region of the spinal cord. These results indicate that GalC and sulfatide play important roles in myelin function and stability.
Mammalian sulfoglycolipids comprise two major members, sulfatide (HSO3-3-galactosylceramide) and seminolipid (HSO3-3-monogalactosylalkylacylglycerol). Sulfatide is a major lipid component of the myelin sheath and serves as the epitope for the well known oligodendrocyte-marker antibody O4. Seminolipid is synthesized in spermatocytes and maintained in the subsequent germ cell stages. Both sulfoglycolipids can be synthesized in vitro by using the isolated cerebroside sulfotransferase. To investigate the physiological role of sulfoglycolipids and to determine whether sulfatide and seminolipid are biosynthesized in vivo by a single sulfotransferase, Cst-null mice were generated by gene targeting. Cst ؊/؊ mice lacked sulfatide in brain and seminolipid in testis, proving that a single gene copy is responsible for their biosynthesis. Cst ؊/؊ mice were born healthy, but began to display hindlimb weakness by 6 weeks of age and subsequently showed a pronounced tremor and progressive ataxia. Although compact myelin was preserved, Cst ؊/؊ mice displayed abnormalities in paranodal junctions. On the other hand, Cst ؊/؊ males were sterile because of a block in spermatogenesis before the first meiotic division, whereas females were able to breed. These data show a critical role for sulfoglycolipids in myelin function and spermatogenesis.
The evolutionary demand for rapid nerve impulse conduction led to the process of myelinationdependent organization of axons into distinct molecular domains. These domains include the node of Ranvier flanked by highly specialized paranodal domains where myelin loops and axolemma orchestrate the axoglial septate junctions. These junctions are formed by interactions between a glial isoform of neurofascin (Nfasc NF155 ) and axonal Caspr and Cont. Here we report the generation of myelinating glia-specific Nfasc NF155 null mouse mutants. These mice exhibit severe ataxia, motor paresis, and death before the third postnatal week. In the absence of glial Nfasc NF155 , paranodal axoglial junctions fail to form, axonal domains fail to segregate, and myelinated axons undergo degeneration. Electrophysiological measurements of peripheral nerves from Nfasc NF155 mutants revealed dramatic reductions in nerve conduction velocities. By using inducible PLP-CreER recombinase to ablate Nfasc NF155 in adult myelinating glia, we demonstrate that paranodal axoglial junctions disorganize gradually as the levels of Nfasc NF155 protein at the paranodes begin to drop. This coincides with the loss of the paranodal region and concomitant disorganization of the axonal domains. Our results provide the first direct evidence that the maintenance of axonal domains requires the fence function of the paranodal axoglial junctions. Together, our studies establish a central role for paranodal axoglial junctions in both the organization and the maintenance of axonal domains in myelinated axons. The anatomical organization of myelinated axons into distinct molecular domains is the basis for rapid propagation of action potentials in a saltatory manner (Hartline and Colman, 2007). Although the signal transduction mechanisms that underlie the axonal organization into specific domains (i.e., the node, the paranode, the juxtaparanode, and the internode) are poorly understood, considerable progress has been made in identifying key molecular components within these axonal domains. The paranodal region is unique in its organization and ultrastructural characteristics and contains specialized axoglial junctions referred to as the paranodal axoglial septate junctions, which resemble the ladder-like invertebrate septate junctions (Einheber et al., 1997;Pedraza et al., 2001; Banerjee et al., 2006a, b). Three major paranodal proteins have been identified: Caspr or paranodin (Einheber et al., 1997;Menegoz et al., 1997;Peles et al., 1997;Bhat et al., 2001), and a GPI-anchored neural cell adhesion molecule Contactin (Cont;Berglund et al., 1999;Boyle et al., 2001) on the axonal side, and the 155-kDa neurofascin isoform (Nfasc NF155 ) on the glial side (Tait et al., 2000;Charles et al., 2002). Although Nfasc NF155 is the only known glial paranodal protein, many proteins expressed in myelinating glia are required at some level in the formation and/or stability of the paranodal junctions (Coetzee et al., 1996;Griffiths et al., 1998;Ishibashi et al., 2002; LappeSie...
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