Oxygen sensitive synaptic neurotransmission in anoxia-tolerant turtle cerebrocortex.

Anoxia rapidly elicits hyper-excitability and cell death in mammal brain but this is not so in anoxia-tolerant turtle brain where spontaneous electrical activity is suppressed by anoxia (i.e. spike arrest; SA). In anoxic turtle brain extracellular GABA concentrations increase dramatically and impact GABAergic synaptic transmission in a way that results in SA. Here we briefly review what is known about the regulation of glutamatergic signalling during anoxia and investigate the possibility that in anoxic turtle cortical neurons GABA(A/B) receptors play an important role in neuroprotection. Both AMPA and NMDA receptor currents decrease by about 50% in anoxic turtle cerebrocortex and therefore exhibit channel arrest, whereas GABA-A receptor currents increase twofold and increase whole-cell conductance. The increased post synaptic GABA-A receptor current is contrary to the channel arrest hypothesis but it does serve an important function. The reversal potential of the GABA-A receptor (E(GABA)) is only slightly depolarized relative to the resting membrane potential of the neuron and not sufficient to elicit an action potential. Therefore, when GABA-A receptors are activated, membrane potential moves to E(GABA) and prevents further depolarization by glutamatergic inputs during anoxia by a process termed shunting inhibition. Furthermore we discuss the presynaptic role of GABA-B receptors and show that increased endogenous GABA release during anoxia mediates SA by activating both GABA-A and B receptors and that this represents a natural oxygen-sensitive adaptive mechanism to protect brain from anoxic injury.

Heart mitochondria from naked mole-rats (Heterocephalus glaber) are more coupled, but similarly susceptible to anoxia-reoxygenation stress than in laboratory mice (Mus musculus).

Naked mole-rats (Heterocephalus glaber; NMRs) are among the most hypoxia-tolerant mammals described to date and exhibit plastic responses during hypoxia exposure. The goal of the present study was to determine if heart mitochondria from NMRs functionally differ from those of hypoxia-intolerant common laboratory mice (Mus musculus). We assessed heart mitochondrial respiratory flux, proton leak kinetics, responses to in vitro anoxia-recovery, and maximal complex enzyme activities. When investigated at their respective body temperatures (28 °C for NMR and 37 °C for mice), NMR heart mitochondria had lower respiratory fluxes relative to mice, particularly for state 2 and oligomycin-induced state 4 leak respiration rates. When leak respiration rates were standardized to the same membrane potential, NMR mitochondria had lower complex II-stimulated state 2 respiration rates than mice. Both mice and NMRs responded similarly to an in vitro anoxia-recovery challenge and decreased state 3 respiration rate post-anoxia. Finally, NMRs had overall lower maximal complex enzyme activities compared with mice, but the magnitude of the difference did not correspond with observed differences in respiratory fluxes. Overall, heart mitochondria from NMRs appear more coupled than those of mice, but in both species the heart appears equally susceptible to ischemic-reperfusion injury.

Adaptive responses of vertebrate neurons to anoxia--matching supply to demand.

Oxygen depleted environments are relatively common on earth and represent both a challenge and an opportunity to organisms that survive there. A commonly observed survival strategy to this kind of stress is a lowering of metabolic rate or metabolic depression. Whether metabolic rate is at a normal or a depressed level the supply of ATP (glycolysis and oxidative phosphorylation) must match the cellular demand for ATP (protein synthesis and ion pumping), a condition that must of course be met for long-term survival in hypoxic and anoxic environments. Underlying a decrease in metabolic rate is a corresponding decrease in both ATP supply and ATP demand pathways setting a new lower level for ATP turnover. Both sides of this equation can be actively regulated by second messenger pathways but it is less clear if they are regulated differentially or even sequentially with the onset of anoxia. The vertebrate brain is extremely sensitive to low oxygen levels yet some species can survive in oxygen depleted environments for extended periods and offer a working model of brain survival without oxygen. Hypoxia tolerant vertebrate brain will be the primary focus of this review; however, we will draw upon research involving hypoxia/ischemia tolerance mechanisms in liver and heart to offer clues to how brain can tolerate anoxia. The issue of regulating ATP supply or demand pathways will also be addressed with a focus on ion channel arrest being a significant mechanism to reduce ATP demand and therefore metabolic rate. Furthermore, mitochondria are ideally situated to serve as cellular oxygen sensors and mediator of protective mechanisms such as ion channel arrest. Therefore, we will also describe a mitochondria based mechanism of ion channel arrest involving ATP-sensitive mitochondrial K(+) channels, cytosolic calcium and reaction oxygen species concentrations.