The Mechanism of NMDA Receptor Hyperexcitation in High Pressure Helium and Hyperbaric Oxygen

Abstract

Professional divers exposed to pressures greater than 1.1 MPa may suffer from the high pressure neurological syndrome (HPNS). Divers who use closed-circuit breathing apparatus face the risk of CNS hyperbaric oxygen toxicity (HBOTox). Both syndromes are characterized by reversible CNS hyperexcitability, accompanied by cognitive and motor deficits. Previous studies have demonstrated that the hyperexcitability of HPNS is induced mainly by NMDA receptors (NMDARs). In our recent studies, we demonstrated that the response of NMDARs containing GluN1 + GluN2A subunits was increased by up to 50% at high pressure (HP) He, whereas GluN1 + GluN2B NMDARs response was not affected under similar conditions. Our aim was to compare the responses of both types of NMDARs under HBOTox conditions to those of HP He and to reveal their possible underlying molecular mechanism(s). The two combinations of NMDARs were expressed in Xenopus laevis oocytes, placed in a pressure chamber, voltage-clamped, and their currents were tested at 0.1 (control) −0.54 MPa 100% O 2 or 0.1-5.1 MPa He pressures. We show, for the first time, that NMDARs containing the GluN2A subunit exhibit increased responses in 100% O 2 at a pressure of 0.54 MPa, similar to those observed in 5.1 MPa He. In contrast, the GluN1 + GluN2B response is not sensitive to either condition. We discovered that neither condition produced statistically significant changes in the voltage-dependent Mg 2+ inhibition of the response. The averaged IC 50 remained the same, but a higher [Mg 2+ ] o was required to restore the current to its control value. The application of TPEN, a Zn 2+ chelator, in control, HP He and HBOTox conditions, revealed that the increase in GluN1 + GluN2A current is associated with the removal of the high-affinity voltage-independent Zn 2+ inhibition of the receptor. We propose that HPNS and HBOTox may share a common mechanism, namely removal of Zn 2+ from its specific binding site on the N-terminal domain of the GluN2A subunit, which increases the pore input-conductance and produces larger currents and consequently a hyperexcitation.

Impact of Hyperbaric Oxygen Therapy on Cognitive Functions: a Systematic Review

“…For instance, it has been proposed that HBOT may act as a transducer to improve oxidative metabolism while subsequent normobaric oxygen therapy (100% oxygen, 1 ATA) may further enhance this effect (Rockswold et al, 2010 , 2013 ). Exposure of rat brain slices to high pressures (5.3 ATA) typically shows an augmentation in the synaptic NMDA receptors response, usually followed by post-synaptic excitability modifications (Bliznyuk et al, 2020 ; Mor & Grossman, 2010 ; Mor & Grossman, 2007 ). HBOT and normobaric reoxygenation augment excitability and activate oxygen-induced potentiation in CA1 hippocampal neurons (Garcia et al, 2010b ).…”

Does hyperbaric oxygen cause narcosis or hyperexcitability? A quantitative EEG analysis

“…A recent in vitro study demonstrated that 507 kPa of oxygen caused a significant increase in response amplitude of a specific NMDA receptor subunit (GluN2A), while lower pressures showed a linear trend toward the same effect (Bliznyuk et al, 2020). These subunits are highly expressed in the cortex and hippocampus (Sanz‐Clemente et al, 2012), and hippocampal expression is associated with learning and memory consolidation (Cercato et al, 2017).…”

Role of NMDA Receptor in High-Pressure Neurological Syndrome and Hyperbaric Oxygen Toxicity

“…It is commonly accepted that the general mechanism underlying HBOTx is probably oxidative stress, namely the presence of high levels of reactive oxygen species (ROS) that may damage any human biological system [29]. However, recently, we have shown that HPNS and HBOTx may share a common mechanism in which NMDAR plays a crucial role [30] (see below).…”