Cellular and neurophysiological effects of high ambient pressure.
The observed cellular effects of pressure are entirely compatible with the acute manifestations of CNS hyperexcitability. Inhibition of the glycine receptor will reduce post-synaptic inhibition, leading to increased excitability (cf 'Startle Disease', an hereditary disease with increased excitability arising from a genetic modification to the glycine receptor (Becker et al., 2002)). Since glycine-mediated neurotransmission is particularly associated with motor reflex circuits (Lynch, 2004) it is not surprising that many of the acute manifestations of pressure involve motor dysfunction. Potentiation by pressure of the NR1-NR2C subtype of the NMDA-sensitive glutamate receptor will lead to increased excitability within the cerebellum (where this receptor sub-type is most highly expressed (Monyer et al., 1994)). Although the cerebellum receives input from many parts of the nervous system, it projects primarily to the motor and frontal lobe cognitive areas. Thus dysfunction of the glutamate-mediated excitatory neurotransmission in this area is most likely to result in locomotor and cognitive symptoms, characteristic of acute pressure effects. Finally, the effects observed on AC/cAMP intracellular signalling, probably mediated via dopamine receptors, is also likely to produce motor dysfunction (cf Parkinson's disease). The observed cellular effects also suggest potential mechanisms that could result in long-term CNS dysfunction. Potentiation of glutamate neurotransmission is likely to lead to excessive calcium entry into those neurons. This may trigger excitotoxicity via a signal cascade in which neuronal NO synthase is activated producing the toxic free radical peroxynitrite and activation of the proapoptotic protein poly(ADP-ribose) polymerase (Aarts & Tymianski, 2005). An additional mechanism, also initially triggered by a rise in intracellular calcium through NR1-NR2C receptors, involves activation of a member of the Transient Receptor Potential (TRP) channel superfamily, the TRPM-7 channel. Activation of these channels will cause a further rise in intracellular calcium, creating a positive feedback and generating more neuronal death through the toxic signal cascade (Aarts & Tymianski, 2005). Neuronal cell death within the cerebellum might be expected to give rise to delayed motor and cognitive dysfunction the magnitude of which would tend to be related to the extent of hyperbaric exposure. There is at present no evidence that these excitotoxic mechanisms are triggered by exposure to pressure but future experimental work should investigate the extent to which pressure might activate them.
Daniels
S
S
Welsh School of Pharmacy, Cardiff University, UK.
D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D006610:High Pressure Neurological Syndrome / Q000503:physiopathology; D006801:Humans; D007473:Ion Channels / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology; D011312:Pressure / Q000009:adverse effects*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D017470:Receptors, Glutamate / Q000502:physiology; D017981:Receptors, Neurotransmitter / Q000502:physiology*; D015222:Sodium Channels / Q000502:physiology
D015220:Calcium Channels; D007473:Ion Channels; D015221:Potassium Channels; D043562:Receptors, G-Protein-Coupled; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter; D015222:Sodium Channels