Primary cerebral and cerebellar astrocytes display differential sensitivity to extracellular sodium with significant effects on apoptosis.

Central pontine myelinolysis is one of the idiopathic or iatrogenic brain dysfunction, and the most common cause is excessively rapid correction of chronic hyponatraemia. While myelin disruption is the main pathology, as the diagnostic name indicates, a previous study has reported that astrocyte death precedes the destruction of the myelin sheath after the rapid correction of chronic low Na(+) levels, and interestingly, certain brain regions (cerebral cortex, hippocampus, etc.) are specifically damaged but not cerebellum. Here, using primary astrocyte cultures derived from rat cerebral cortex and cerebellum, we examined how extracellular Na(+) alterations affect astrocyte death and whether the response is different between the two populations of astrocytes. Twice the amount of extracellular [Na(+) ] and voltage-gated Na(+) channel opening induced substantial apoptosis in both populations of astrocytes, while, in contrast, one half [Na(+) ] prevented apoptosis in cerebellar astrocytes, in which the Na(+) -Ca(2+) exchanger, NCX2, was highly expressed but not in cerebral astrocytes. Strikingly, the rapid correction of chronic one half [Na(+) ] exposure significantly increased apoptosis in cerebellar astrocytes but not in cerebral astrocytes. These results indicate that extracellular [Na(+) ] affects astrocyte apoptosis, and the response to alterations in [Na(+) ] is dependent on the brain region from which the astrocyte is derived.

Oligodendrocyte plasticity with an intact cell body in vitro.

Demyelination is generally regarded as a consequence of oligodendrocytic cell death. Oligodendrocyte processes that form myelin sheaths may, however, degenerate and regenerate independently of the cell body, in which case cell death does not necessarily occur. We provide here the first evidence of retraction and regeneration of oligodendrocyte processes with no cell death in vitro, using time-lapse imaging. When processes were severed mechanically in vitro, the cells did not undergo cell death and the processes regenerated in 36 h. In a separate experiment, moderate N-methyl-D-aspartate (NMDA) stimuli caused process retraction without apparent cell death, and the processes regained their elaborate morphology after NMDA was removed from the culture medium. These results strongly suggest that demyelination and remyelination can take place without concomitant cell death, at least in vitro. Process regeneration may therefore become a target for future therapy of demyelinating disorders.

Demyelination in the juvenile period, but not in adulthood, leads to long-lasting cognitive impairment and deficient social interaction in mice.

BACKGROUND: Dysmyelination is hypothesized to be one of the causes of schizophrenic symptoms. Supporting this hypothesis, demyelination induced by cuprizone was recently shown to cause schizophrenia-like symptoms in adult rodents [Xiao L, Xu H, Zhang Y, Wei Z, He J, Jiang W, et al. Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes. Mol Psychiatry 2008;13:697-708]. The present study asked if the timing of demyelination (i.e., juvenile period or adulthood) influenced abnormal behavior. METHODS: B57BL/6 mice were fed with 0.2% cuprizone either from postnatal day 29 (P29) to P56 (early demyelination group) or from P57 to P84 (late demyelination group), and then returned to normal mouse chow until P126, when the behavioral analysis was initiated. RESULTS: In both groups, the intake of cuprizone for 28 days produced massive demyelination in the corpus callosum by the end of the treatment period, and subsequent normal feeding restored myelination by P126. In a Y-maze test, the spatial working memory was impaired in both groups right after the cuprizone feeding ceased, consistent with previous studies, whereas only the early demyelination group exhibited impaired working memory after remyelination took place. In an open field test, social interactions were decreased in the early demyelination group, but not in the late group. Novel cognition and anxiety-related behaviors were comparable between the two groups. CONCLUSIONS: Our findings suggest that the timing of demyelination has substantial impacts on behaviors of adult mice.