title: Exercise Prevents Amyloid-β-Induced Hippocampal Network Disruption by Inhibiting GSK3β Activation.
abstract: Exercise is becoming a promising therapeutic approach to prevent alterations both in Alzheimer's disease (AD) patients and in transgenic models of AD. This neuroprotection has been associated with changes in hippocampal structure and function, as well as with the reduction of amyloid-β (Aβ) production and accumulation. However, whether exercise produces lasting changes in hippocampal population activity and renders it resistant to Aβ-induced network dysfunction is still unknown. Thus, we tested whether voluntary exercise changes hippocampal population activity and prevents its alteration in the presence of Aβ, which has been associated to glycogen synthase kinase-3β (GSK3β) activation. We found that the hippocampal population activity recorded in slices obtained from mice that exercised voluntarily (with free access to a running wheel for 21 days) exhibits higher power and faster frequency composition than slices obtained from sedentary animals. Moreover, the hippocampal network of mice that exercised becomes insensitive to Aβ-induced inhibition of spontaneous population activity. This protective effect correlates with the inability of Aβ to activate GSK3β, is mimicked by GSK3β inhibition with SB126763 (in slices obtained from sedentary mice), and is abolished by the inhibition of PI3K with LY294002 (in slices obtained from mice that exercised). We conclude that voluntary exercise produces a lasting protective state in the hippocampus, maintained in hippocampal slices by a PI3K-dependent mechanism that precludes its functional disruption in the presence of Aβ by avoiding GSK3β activation.
authors.affiliation: Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, México.
authors.forename: Arturo G
authors.initials: AG
authors.lastname: Isla
authors.affiliation: Departamento de Neurobiología Molecular y Celular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, México.
authors.forename: Francisco Gabriel
authors.initials: FG
authors.lastname: Vázquez-Cuevas
authors.affiliation: Departamento de Neurobiología del Desarrollo y Neurofisiología, Instituto de Neurobiología, Universidad Nacional Autónoma de México, México.
authors.forename: Fernando
authors.initials: F
authors.lastname: Peña-Ortega
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008839:Microelectrodes; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000502:physiology*; D010446:Peptide Fragments / Q000633:toxicity*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D046509:Tissue Culture Techniques; D014836:Volition
chemical_list: D016229:Amyloid beta-Peptides; D002867:Chromones; D004791:Enzyme Inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D009025:Morpholines; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C075222:amyloid beta-protein (1-42); C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C000605507:Gsk3b protein, mouse
keywords: Amyloid-β; GSK3β; PI3K; hippocampus; spontaneous population activity; voluntary-exercise