title: Hypoxia/reoxygenation impairs memory formation via adenosine-dependent activation of caspase 1.
abstract: After hypoxia, a critical adverse outcome is the inability to create new memories. How anterograde amnesia develops or resolves remains elusive, but a link to brain-based IL-1 is suggested due to the vital role of IL-1 in both learning and brain injury. We examined memory formation in mice exposed to acute hypoxia. After reoxygenation, memory recall recovered faster than memory formation, impacting novel object recognition and cued fear conditioning but not spatially cued Y-maze performance. The ability of mice to form new memories after hypoxia/reoxygenation was accelerated in IL-1 receptor 1 knockout (IL-1R1 KO) mice, in mice receiving IL-1 receptor antagonist (IL-1RA), and in mice given the caspase 1 inhibitor Ac-YVAD-CMK. Mechanistically, hypoxia/reoxygenation more than doubled caspase 1 activity in the brain, which was localized to the amygdala compared to the hippocampus. This reoxygenation-dependent activation of caspase 1 was prevented by broad-spectrum adenosine receptor (AR) antagonism with caffeine and by targeted A1/A2A AR antagonism with 8-cyclopentyl-1,3-dipropylxanthine plus 3,7-dimethyl-1-propargylxanthine. Additionally, perfusion of adenosine activated caspase 1 in the brain, while caffeine blocked this action by adenosine. Finally, resolution of anterograde amnesia was improved by both caffeine and by targeted A1/A2A AR antagonism. These findings indicate that amygdala-based anterograde amnesia after hypoxia/reoxygenation is sustained by IL-1β generated through adenosine-dependent activation of caspase 1 after reoxygenation.
authors.affiliation: Division of Nutritional Sciences, Program in Integrative Immunology and Behavior, University of Illinois, Urbana Illinois 61801, USA.
authors.forename: Gabriel S
authors.initials: GS
authors.lastname: Chiu
authors.forename: Diptaman
authors.initials: D
authors.lastname: Chatterjee
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Darmody
authors.forename: John P
authors.initials: JP
authors.lastname: Walsh
authors.forename: Daryl D
authors.initials: DD
authors.lastname: Meling
authors.forename: Rodney W
authors.initials: RW
authors.lastname: Johnson
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Freund
mesh_terms: D000241:Adenosine / Q000494:pharmacology / Q000502:physiology*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D020324:Amnesia, Anterograde / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D000679:Amygdala / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D020170:Caspase 1 / Q000187:drug effects / Q000502:physiology*; D061945:Caspase Inhibitors / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D003463:Cues; D004789:Enzyme Activation; D005239:Fear / Q000187:drug effects / Q000502:physiology; D002534:Hypoxia, Brain / Q000150:complications* / Q000503:physiopathology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D011939:Mental Recall; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D053573:Receptors, Interleukin-1 Type I / Q000172:deficiency; D018047:Receptors, Purinergic P1 / Q000502:physiology; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D013805:Theobromine / Q000031:analogs & derivatives / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D053590:Interleukin 1 Receptor Antagonist Protein; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D053573:Receptors, Interleukin-1 Type I; D018047:Receptors, Purinergic P1; D014970:Xanthines; D002110:Caffeine; C057837:3,7-dimethyl-1-propargylxanthine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D020170:Caspase 1; D000241:Adenosine; D013805:Theobromine; D010100:Oxygen