Two temporal stages of oligodendroglial response to excitotoxic lesion in the gray matter of the adult rat brain

Excitotoxic lesions in the gray matter induce profuse demyelination of pass age and afferent fibers in areas of neuronal loss, independent of Wallerian degeneration. The time course of this phenomenon, which extends over weeks after the excitotoxin injection, suggests that demyelination is not relate d only to a direct effect of the toxin. In order to define mechanisms at wo rk, a parallel study of myelin and oligodendrocytes was carried out followi ng kainate injections into the adult rat thalamus. Within the Ist day postl esion, myelin alteration appeared throughout the area exhibiting neuronal l oss, while the number of oligodendrocytes fell by 45%. No apoptotic oligode ndrocytes were identified at that time. Over the following 2 days, there wa s no further loss of myelin and oligodendrocytes, but there was an increase in the number of oligodendrocytes displaying typical signs of apoptosis as revealed with TUNEL-end-labeled nuclei, Hoechst-labeled condensed chromati n bodies, or bax immunoreactivity. This resulted in a second, progressive l oss of both myelin and oligodendrocytes leading to their almost complete di sappearance 2 weeks postlesion. These results demonstrate two temporal stag es of oligodendroglial cell death. The excitotoxin injection resulted in th e rapid destruction of a first oligodendroglial population, most probably b y necrosis. A second population died in a delayed manner from apoptosis. Th is second wave of death coincided with an activated microglia/macrophage in vasion of the lesion, suggesting that delayed oligodendroglial death result s from toxic microglia/macrophage effects. In addition, the longest survivi ng oligodendrocytes were located next to reactive astrocytes, suggesting th e existence of trophic interactions between these two glial populations. (C ) 2001 Academic Press.