title: Similar cation channels mediate protection from cerebellar exitotoxicity by exercise and inheritance.
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\xE2\x80\x90toxicity 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.
authors.affiliation: Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Shani
authors.initials: S
authors.lastname: Ben-Ari
authors.forename: Keren
authors.initials: K
authors.lastname: Ofek
authors.forename: Shahar
authors.initials: S
authors.lastname: Barbash
authors.forename: Hanoch
authors.initials: H
authors.lastname: Meiri
authors.forename: Eugenia
authors.initials: E
authors.lastname: Kovalev
authors.forename: David Samuel
authors.initials: DS
authors.lastname: Greenberg
authors.forename: Hermona
authors.initials: H
authors.lastname: Soreq
authors.forename: Shai
authors.initials: S
authors.lastname: Shoham
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D020869:Gene Expression Profiling; D005971:Glutamates / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007276:Injections, Intraventricular; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010805:Physical Conditioning, Animal; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism; D051637:Shaker Superfamily of Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020521:Stroke / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015854:Up-Regulation
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D018690:Excitatory Amino Acid Agonists; D005971:Glutamates; C578665:HCN1 protein, human; C578666:Hcn1 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D054086:KATP Channels; C101328:Kcnab2 protein, mouse; D015221:Potassium Channels; D017470:Receptors, Glutamate; D051637:Shaker Superfamily of Potassium Channels; C092520:uK-ATP-1 potassium channel; D007608:Kainic Acid; D005905:Glyburide