Sip1 mutation suppresses the resistance of cerebral cortex neurons to hypoxia through the disturbance of mechanisms of hypoxic preconditioning

Abstract

Mutation of Sip1 plays a key role in pathogenesis of the Mowat–Wilson syndrome characterized by the presence of pronounced epileptic signs in patients. As a rule, neurodegenerative processes are accompanied by hypoxic phenomena, glutamate toxicity, and death of nerve cells. The molecular mechanisms underlying these phenomena are multifaceted and complex. Hypoxia causes the leakage of glutamate and other neurotransmitters and thus activates glutamate receptors and channels of plasma membrane. Hypoxia is accompanied by increased synthesis and secretion of proteins-regulators of oxidative stress, inflammation, apoptosis, and synaptic transmission. In this work, we investigated the effect of Sip1 mutations on the neuronal sensitivity of the brain to hypoxia and the formation of the hypoxic preconditioning phenomenon. The preconditioning effect was evaluated by the degree of suppressing activity of NMDA receptors by hypoxic episodes. Using fluorescent microscopy, we showed that cortical neurons from the brain of heterozygous (Sip1^wt/fI) and homozygous (Sip1^fI/fI) mice are characterized by the absence of the hypoxic preconditioning effect, whereas in Sip1^wt/wt neurons the amplitudes of Ca²⁺ responses to the application of NMDA are suppressed after transient episodes of hypoxia. In addition, hypoxia exerted a significant toxic effect on Sip1fI/fI neurons, which was manifested not only by an increased sensitivity to a decrease of the oxygen partial pressure (pO₂) and increased amplitudes of Ca2+ responses to application of NMDA after each hypoxic episode, but also by death of a considerable number of cells.