Abstract
Ischemic stroke is a major cause of death and long-term disability. We demonstrate that middle cerebral artery occlusion (MCAO) in mice leads to a strong decline in dendritic arborization of penumbral neurons. These defects were subsequently repaired by an ipsilateral recovery process requiring the actin nucleator Cobl. Ischemic stroke and excitotoxicity, caused by calpain-mediated proteolysis, significantly reduced Cobl levels. In an apparently unique manner among excitotoxicity-affected proteins, this Cobl decline was rapidly restored by increased mRNA expression and Cobl then played a pivotal role in poststroke dendritic arbor repair in peri-infarct areas. In Cobl knockout (KO) mice, the dendritic repair window determined to span day 2 to 4 poststroke in wild-type (WT) strikingly passed without any dendritic regrowth. Instead, Cobl KO penumbral neurons of the primary motor cortex continued to show the dendritic impairments caused by stroke. Our results thereby highlight a powerful poststroke recovery process and identified causal molecular mechanisms critical during poststroke repair.
Highlights
Five million people remain permanently disabled after stroke each year
Quantitative biochemical analyses of brain lysates of mice subjected to ischemic stroke by middle cerebral artery occlusion (MCAO) (Fig 1A–1P) showed a reduction of Cobl protein levels at the ipsilateral side
We evaluated whether the massive MCAO-induced impairment in dendritic arborization we observed in the M1 (Fig 4) was permanent and part of the lesion-based disabilities caused
Summary
Stroke leads to a loss of neurons and neuronal network connections due to lack of energy, excitotoxicity, oxidative stress, inflammation, and apoptosis as pathophysiological events [1]. The relative lesion size of survivable human stroke is usually limited to a few percent of the brain [5]. In mice, such damages are very well resembled by 30-minute induced MCAO. By contrast, prolonged paradigms do not resemble survivable human strokes, as they lead to a loss of large parts of the entire hemisphere affected and to significant structural changes at distant or even contralateral sites [5,6,7]
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