CNS wound healing is severely depressed in metallothionein I and II-deficient mice

To characterize the physiological role of metallothioneins I and II (MT-I+I I) in the brain, we have examined the chronological effects of a freeze inj ury to the cortex in normal and MT-I+II null mice. In normal mice, microgli a/macrophage activation and astrocytosis were observed in the areas surroun ding the lesion site, peaking at similar to 1 and 3 d postlesion (dpl), res pectively. At 20 dpI, the parenchyma had regenerated. Both brain macrophage s and astrocytes surrounding the lesion increased the MT-I+II immunoreactiv ity, peaking at similar to 3 dpl, and at 20 dpl it was similar to that of u nlesioned mice. In situ hybridization analysis indicates that MT-I+II immun oreactivity reflects changes in the messenger levels. In MT-I+II null mice, microglia/macrophages infiltrated the lesion heavily, and at 20 dpl they w ere still present. Reactive astrocytosis was delayed and persisted at 20 oc curred. The rate of apoptosis, as determined by using terminal deoxynucleot idyl transferase-mediated dUTP-biotin nick end labeling, was drastically in creased in neurons of ipsilateral cortex of the MT-I+II null mice. Our resu lts demonstrate that MT-I+II are essential for a normal wound repair in the CNS, and that their deficiency impairs neuronal survival.