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-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.

Gene expression patterns in the hippocampus during the development and aging of Glud1(Glutamate Dehydrogenase 1) transgenic and wild type mice

“…Mutations in these two genes are associated with early onset epileptic seizures [ 38 , 39 ]. A third potassium channel gene was Kcnab2 , a gene that codes for the beta subunit of voltage-gated potassium channels and whose over-expression protects neurons from Glu-induced cell damage [ 40 ] while its under-expression impedes associative memory formation [ 41 ].…”

Delayed Exercise-Induced Functional and Neurochemical Partial Restoration Following MPTP

“…Certainly, the major conclusion is that the earlier the exercise intervention is introduced, the better the prognosis for the patients. Studies on the influence of exercise intervention in traumatic brain injury (TBI) provide interesting comparisons because several studies have shown that physical exercise already during the pre-insult, whether mechanical, fluid, or neurotoxic, protects against disorders resulting from neuroinflammation, apoptosis, blood-brain barrier breakdown, excitotoxins, and functional parameters (Ben-Ari et al 2011;Hassett et al 2011;Itoh et al 2011). In each case, the intimate role of the neurotrophin, brain-derived neurotrophic factor (BDNF) linked to neurogenesis, neuronal survival, and neuroreparation in the brain and CNS (Numakawa et al 2010), appears an essential ingredient in the effects of exercise (Macias et al 2009).…”

Potential Role of Exercise in Retinal Health

“…[24][25][26][27][28][29] Centrally, the rehabilitative effects of exercise are well documented in models that span stroke to PD to normal aging, 7-10 including in CNS structures that are not considered regenerative, such as substantia nigra and basal ganglia, 30-32 corticostriatal synapses, 33 and cerebellum. 34 …”