To characterize the physiological role of metallothioneins I and II (MT-IϩII) in the brain, we have examined the chronological effects of a freeze injury to the cortex in normal and MT-IϩII null mice. In normal mice, microglia/macrophage activation and astrocytosis were observed in the areas surrounding the lesion site, peaking at ϳ1 and 3 d postlesion (dpl), respectively. At 20 dpl, the parenchyma had regenerated. Both brain macrophages and astrocytes surrounding the lesion increased the

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... I immunoreactivity, peaking at ϳ3 dpl, and at 20 dpl it was similar to that of unlesioned mice. In situ hybridization analysis indicates that MT-IϩII immunoreactivity reflects changes in the messenger levels. In MT-IϩII null mice, microglia/macrophages infiltrated the lesion heavily, and at 20 dpl they were still present. Reactive astrocytosis was delayed and persisted at 20 dpl. In contrast to normal mice, at 20 dpl no wound healing had occurred. The rate of apoptosis, as determined by using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, was drastically increased in neurons of ipsilateral cortex of the MT-IϩII null mice. Our results demonstrate that MT-IϩII are essential for a normal wound repair in the CNS, and that their deficiency impairs neuronal survival.