title: Short-term episodes of hypoxia induce posthypoxic hyperexcitability and selective death of GABAergic hippocampal neurons.
abstract: We have previously developed a rat hippocampal neuronal cell model for the registration of the preconditioning effect and posthypoxic hyperexcitability (Turovskaya et al., 2011). Repeated episodes of short-term hypoxia are reported to suppress the amplitude of Ca(2+) response to NMDA in majority of neurons, reflecting the effect of preconditioning in the culture. In addition, exposure to hypoxia causes posthypoxic hyperexcitability: this is characterized by the onset of spontaneous synchronous Ca(2+) transients in a population of neurons in a neural network during the period of reoxygenation after each hypoxic episode. The nature of this phenomenon is unknown, although it has been observed that there always exists a minority of neurons in which there is no effect of hypoxic preconditioning. In this small population of neurons, the amplitude of Ca(2+) response to NMDA is not suppressed, but rather increases after each episode of hypoxia. Here we report the type of these neurons and their role in the generation of posthypoxic hyperexcitability. We compared the effect of short-term hypoxia on the amplitude of the Ca(2+) response to NMDA and the Ca(2+) transient generation in two populations of neurons - inhibitory GABAergic and excitatory glutamatergic. We have demonstrated that the neurons in which the preconditioning effect was not observed are GABAergic. Moreover at the instant moment of the posthypoxic synchronous Ca(2+)-transient generation (during reoxygenation) there is a global increase of [Ca(2+)]i and subsequent apoptosis in some GABAergic neurons. Anti-inflammatory cytokine interleukin-10 prevents the development of posthypoxic hyperexcitability, inhibiting the spontaneous synchronous Ca(2+) transients. At the same time, interleukin-10 protects GABAergic neurons from death, by restoring the effect of hypoxic preconditioning in them. Activation of one of the signaling pathways initiated by interleukin-10 appears to be necessary for the development of hypoxic preconditioning in GABAergic neurons. Overall our results indicate that short-term episodes of hypoxia can damage GABAergic neurons and weaken the inhibitory action of GABAergic neurons in a neural network. Activation of PI3K-dependent survival signaling pathways in neurons of this type is a possible strategy to protect these cells against hypoxia.
authors.affiliation: Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Russia.
authors.forename: Egor A
authors.initials: EA
authors.lastname: Turovsky
authors.forename: Maria V
authors.initials: MV
authors.lastname: Turovskaya
authors.forename: Alex V
authors.initials: AV
authors.lastname: Kononov
authors.forename: Valery P
authors.initials: VP
authors.lastname: Zinchenko
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D018846:Excitatory Amino Acids / Q000494:pharmacology; D059330:GABAergic Neurons / Q000378:metabolism / Q000473:pathology*; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D000860:Hypoxia / Q000378:metabolism*; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000378:metabolism*; D019194:Ischemic Preconditioning; D016202:N-Methylaspartate / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D018846:Excitatory Amino Acids; D016753:Interleukin-10; D016202:N-Methylaspartate; D002118:Calcium
keywords: Brief hypoxia; Ca(2+) imaging; Fura-2; GABAergic neurons; Hippocampus; Interleukin-10; NMDA receptors; Posthypoxic hyperexcitability; Precondition