Abstract
Exercise and inherited factors both affect recovery from stroke and head injury, but the underlying mechanisms and interconnections between them are yet unknown. Here, we report that similar cation channels mediate the protective effect of exercise and specific genetic background in a kainate injection model of cerebellar stroke. Microinjection to the cerebellum of the glutamatergic agonist, kainate, creates glutamatergic excito-toxicity characteristic of focal stroke, head injury or alcoholism. Inherited protection and prior exercise were both accompanied by higher cerebellar expression levels of the Kir6.1 ATP-dependent potassium channel in adjacent Bergmann glia, and voltage-gated KVbeta2 and cyclic nucleotide-gated cation HCN1 channels in basket cells. Sedentary FVB/N and exercised C57BL/6 mice both expressed higher levels of these cation channels compared to sedentary C57BL/6 mice, and were both found to be less sensitive to glutamate toxicity. Moreover, blocking ATP-dependent potassium channels with Glibenclamide enhanced kainate-induced cell death in cerebellar slices from the resilient sedentary FVB/N mice. Furthermore, exercise increased the number of acetylcholinesterase-positive fibres in the molecular layer, reduced cerebellar cytokine levels and suppressed serum acetylcholinesterase activity, suggesting anti-inflammatory protection by enhanced cholinergic signalling. Our findings demonstrate for the first time that routine exercise and specific genetic backgrounds confer protection from cerebellar glutamatergic damages by similar molecular mechanisms, including elevated expression of cation channels. In addition, our findings highlight the involvement of the cholinergic anti-inflammatory pathway in insult-inducible cerebellar processes. These mechanisms are likely to play similar roles in other brain regions and injuries as well, opening new venues for targeted research efforts.
Highlights
Many neurological disorders, especially ischemic stroke [1, 2], traumatic brain injuries (TBI) and alcoholism, involve glutamatergic excitotoxicity to the cerebellum [3]
Neither exercise nor genetic background had an effect on the core region diameter (n ϭ 5–9 per group, P ϭ 0.45 and 0.26, respectively, Student’s t-test, Fig. S1A) In contrast, we found clear differences in the number of calbindin-28K-positive axonal beads, focal pathological swellings characteristic of diverse neuronal malfunctions including ischemic stroke [29], in the penumbra (Fig. 1A-i)
We found that convergent innate and exercise-inducible factors protect the micro-environment of PCs from glutamate excito-toxicity characteristic of stroke and other brain injuries
Summary
Especially ischemic stroke [1, 2], traumatic brain injuries (TBI) and alcoholism, involve glutamatergic excitotoxicity to the cerebellum [3]. High levels of slowly desensitizing AMPA receptors [19] and calcium channels [20] make PCs especially vulnerable to ischemic stroke and glutamate excitotoxicity despite their high content of Ca2ϩ-binding proteins, such as calbindin-28K. Excessive depolarization-induced influx of Ca2ϩ through voltage-gated calcium channels, accompanied by delayed Ca2ϩ release from intracellular stores, results in disruption of axonal delivery and trafficking [21]. This depolarization leads to exaggerated vesicular release, transporter reversal or glutamate liberation after necrotic cell death, preserving harmful high levels of extracellular glutamate [3] and disrupting the cerebellar output to the rest of the brain
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