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Known and unpublished data regarding hyperbaric pressure (HP) effects on voltage dependent-Ca2+ channels (VDCCs) were reviewed in an attempt to elucidate their role in the development of high-pressure neurological syndrome (HPNS). Most postulated effects from studies performed in the last two decades (e.g., depressed maximal current) rely on indirect findings, derived from extracellular [Ca2+] manipulation or by observing Ca(2+)-dependent processes. More recent experiments have tried to directly measure Ca2+ currents under high pressure conditions, some of which are potentially challenging previous indirect findings on one hand, but support findings from work done on neuronal behavior on the other. Additional support for some of the recent findings is provided by computer simulation of pressure effects on a spinal motor neuron activity. HP effect on different types of VDCCs seems to be selective - i.e., HP may suppress, facilitate or not change their activity. Thus, the specific distribution of the various types of the channels in each synaptic terminal or throughout the neuron will determine their function and will influence the neuronal network behavior under HP. Further research is needed in order to fully understand the HPNS etiology.

Human divers exposed to hyperbaric pressure may suffer from cognitive and motor impairments thought to be related to high pressure effects per ce. These effects, termed high pressure neurological syndrome (HPNS), appear at pressure above 1.1 MPa. HPNS involves CNS hyperexcitability that is partially attributed to augmented responses of the glutamatergic N-methyl-d-aspartate receptor (NMDAR). NMDAR is blocked by Mg(2+) (physiologically) and by dl-2-Amino-5-phosphonopentanoic acid (AP5, pharmacologically). We have recently reported that hyperbaric pressure augments rat hippocampus NMDAR synaptic response and generates hyperexcitability. We now test pressure effects on the blockade efficacy of Mg(2+)and AP5. Under high pressure conditions more than double [Mg(2+)](o) and [AP5](o) were needed to achieve similar effects on NMDAR synaptic response's amplitude, decay time, and time integral comparable to control conditions. [Mg(2+)](o) and [AP5](o) concentration-response curves and the concentration for 50% responses' inhibition (IC(50)s) showed similar normalized pattern at control and pressure for each parameter. We conclude that hyperbaric pressure reduces the efficacy of these NMDAR blockers that may be associated with the receptor conformational change(s). This provides additional mechanism for pressure over activation of NMDAR. Taken together with our previous reports, high pressure modification of NMDAR activity significantly contributes to CNS hyperexcitability and possibly for long term vulnerability., (Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

High pressure, which induces central nervous system (CNS) dysfunction (high-pressure neurological syndrome) depresses synaptic transmission at all synapses examined to date. Several lines of evidence indicate an inhibitory effect of pressure on Ca(2+) entry into the presynaptic terminal. In the present work we studied for the first time the effect of pressure on the cerebellar climbing fiber (CF) synaptic responses. Pressure modulation of cerebellar synaptic plasticity was tested in both the CF and parallel fiber (PF) pathways using paired-pulse protocols. CF synapses, which normally operate at a high baseline release probability, demonstrate paired-pulse depression (PPD). High pressure reduced CF synaptic responses at 5.1 and 10.1 MPa but did not affect its PPD. High extracellular Ca(2+) concentration ([Ca(2+)](o)) could not antagonize the effect of pressure on the CF response, whereas low [Ca(2+)](o), in contrast to pressure, decreased both the response amplitude and the observed PPD. PF synapses, which usually operate at low release probability, exhibit paired-pulse facilitation (PPF). Pressure increased PF PPF at all interstimulus intervals (ISIs) tested (20-200 ms). Several Ca(2+) channel blockers as well as low [Ca(2+)](o) could mimic the effect of pressure on the PF response but significantly increased the PPF only at the 20-ms ISI. These results, together with previous data, show that the CF synapse is relatively resistant to pressure. The lack of pressure effect on CF PPD is surprising and may suggest that the PPD is not directly linked to synaptic depletion, as generally suggested. The increase in PPF of the PF at pressure, which is mimicked by Ca(2+) channel blockers or low [Ca(2+)](o), further supports pressure involvement in synaptic release mechanism(s). These results also indicate that pressure effects may be selective for various types of synapses in the CNS.

High pressure (>1.5 MPa) induces a series of disturbances of the nervous system that are generically termed high-pressure nervous syndrome (HPNS). HPNS is characterized by motor and cognitive impairments. The neocortex and the hippocampus are presumably involved in this last disorder. The medial perforant path (MPP) synapse onto the granule cells of the dentate gyrus is the main connection between these structures. We have studied high-pressure (HP) effects on single and frequency response of this synapse. Since effects of HP on various synapses were mimicked by reducing [Ca2+]o, results under these conditions were compared. Medial perforant path-evoked field excitatory postsynaptic potentials (fEPSPs) were recorded from granule cells in rat brain slices. Slices were exposed to high pressure of helium (0.1-10.1 MPa) at 30 degrees C. HP depressed single fEPSPs by 35 and 55% at 5.1 and 10.1 MPa, respectively, and increased paired-pulse facilitation (PPF) at 10- to 40-ms inter-stimulus intervals. Frequency-dependent depression (FDD) was enhanced by HP during trains of stimuli at 50 but not at 25 Hz. Depression of single fEPSPs by reduction of [Ca2+]o from 2 mM control to 1 mM at normal pressure was equivalent to the effect of 10.1 MPa at control [Ca2+]o. However, this low [Ca2+]o induced greater enhancement of PPF, and in contrast, turned FDD at 25-50 Hz into frequency-dependent potentiation. These results suggest that HP depresses single synaptic release by reducing Ca2+ entry, whereas slowing of synaptic frequency response is independent of Ca2+. These findings increase our understanding of HPNS experienced by deep divers.

High pressure induces CNS hyperexcitability while markedly depressing synaptic transmitter release. We studied the effect of pressure (up to 10.1 MPa) on the parallel fibre (PF) synaptic response in biplanar cerebellar slices of adult guinea pigs. Pressure mildly reduced the PF volley amplitude and to a greater extent depressed the excitatory field postsynaptic potential (fPSP). The depression of the PF volley was noted even at supramaximal stimulus intensities, indicating an effect of pressure on the amplitude of the action potential in each axon. Low concentrations of TTX mimicked the effects of pressure on the PF volley without affecting the fPSP. Application omega-conotoxin GVIA (omega-CgTx) reduced the synaptic efficacy by 34.3+/-2.7%. However, in the presence of omega-CgTx the synaptic depression at pressure was significantly reduced. Reduced Ca2+ entry by application of Cd2+ or low [Ca2+]o did not have a similar influence on the effects of pressure. Application of omega-AGA IVA, omega-AGA TK and Funnel-web spider toxin did not affect the synaptic response in concentrations that usually block P-type Ca2+ channels, whilst the N/P/Q-type blocker omega-conotoxin MVIIC reduced the response to 52.7+/-5.0% indicating the involvement of Q-type channels and R-type channels in the non-N-type fraction of Ca2+ entry. The results demonstrate that N-type Ca2+ channels play a crucial role in the induction of PF synaptic depression at pressure. This finding suggests a coherent mechanism for the induction of CNS hyperexcitability at pressure.

1. The cytosolic concentration of a neurotransmitter is believed to be an important factor determining its release. The effects of 3-mercaptopropionic acid (MP) and aminooxyacetic acid (AOAA), glutamate decarboxylase (GAD) blockers, on GABAergic postsynaptic and presynaptic inhibitory neurotransmission were examined in the crayfish (Procambarus clarkii) opener neuromuscular synapses. 2. Intracellular recordings of evoked excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) as well as loose macropatch clamp measurements of excitatory postsynaptic currents (EPSCs) and inhibitory postsynaptic currents (IPSCs) were used to evaluate the effects of the drugs, which were applied exclusively to the nerve bundle. 3. Under normal conditions, a stimulus train to the inhibitor preceding the excitor stimulation elicited a large reduction in EPSP amplitude in a time interval-dependent manner. This inhibition is effected by postsynaptic as well as presynaptic processes. 4. Treatment with MP or AOAA decreased the IPSP amplitude and its altered conductance but had no effect on the IPSP reversal potential or the resting potential of the cell. They did, however, slightly increase the Rin of the fiber. 5. Quantal analysis of single IPSCs revealed that GAD blockers increased the number of failures and thus reduced quantal content (m), diminished the probability of release (p), but did not affect the quantum current (q) or the statistical parameter (n), believed to be the number of available active zones. 6. Quantal analysis of EPSCs, released after interaction with the inhibitor, revealed a reduction in m without any effect on q. GAD blockers greatly reduced the efficacy of this inhibition without affecting the EPSC q. 7. GAD blockers increased the output of the excitor release sites by the following mechanisms: 1) increased EPSC, 2) increased EPSC facilitation, or 3) enhancement of spontaneous activity (miniature EPSCs). 8. Short time incubation with picrotoxin and CGP-35348 eliminated IPSCs and evoked inhibition. However, longer exposure (90 min) increased the excitor responses, similarly to the effects of GAD blockers. 9. Baclofen, a gamma-aminobutyric acid-B (GABAB) agonist, antagonized AOAA effects on evoked inhibition. 10. These results demonstrate that GAD blockers decrease postsynaptic and presynaptic inhibition by reducing both tonic and evoked release, most likely by diminishing p. 11. The reduction in GABA synthesis and release revealed a complex mechanism for GABAergic metabotropic regulation of inhibition efficacy and the release from the excitor glutamatergic terminals.

The cellular mechanisms underlying the effect of high pressure on synaptic transmission at two types of synapses were studied in the opener muscle of the lobster walking leg. Excitatory postsynaptic currents (EPSCs) were recorded using a loose macropatch clamp technique at normal pressure and 3.5, 6.9 MPa helium pressure. Responses of the single excitatory axon could be grouped into two types: low yield (L) synapse exhibiting a small mean EPSC with a considerable number of failures, and high yield (H) synapse having a larger mean EPSC with very few failures. The change in several synaptic transmission parameters indicated that high pressure similarly reduced presynaptic evoked release in both L and H synapses. However, some differences in the kinetics and probability of release could be detected. A major difference was the spontaneous miniature EPSCs (mEPSCs) activity. Many of the mEPSC, observed only in L synapses, were 'giant' (size of 2-5 q). High pressure selectively increased the frequency of the giant mEPSCs in the L synapse but had little effect on their amplitude histogram. High pressure depressed evoked synaptic transmission in both synapses by modulating the presynaptic quantal release parameters, but concomitantly enhanced spontaneous quantal release in L synapses by an unknown mechanism.

The cellular mechanisms underlying the effects of high pressure, GABAergic presynaptic inhibition, and low [Ca2+]0 on glutamatergic excitatory synaptic transmission were studied in the opener muscle of the lobster walking leg. Excitatory postsynaptic currents (EPSCs) were recorded with or without prior stimulation of the inhibitor using a loose macropatch clamp technique at atmospheric pressure and at 6.9 MPA helium pressure. High pressure reduced the mean EPSC amplitude and variance, decreased the quantal content (m), but did not affect the quantum current (q). Pressure shifted the median of the amplitude histogram to the left by 1-2 q. Under normal pressure conditions, presynaptic inhibition and low [Ca2+]0 induced similar effects. However, quantal analysis using a binomial frequency distribution model revealed that high pressure and low [Ca2+]0 diminished n (available active zones) and slightly increased p (probability of release), but presynaptic inhibition reduced p and slightly increased n. At high pressure, presynaptic inhibition was reduced, at which time the major contributor to the inhibitory process appeared to be reduction in n and not p. The similarity of the alterations in quantal parameters of release at high pressure, low [Ca2+]0, and in some conditions of presynaptic inhibition is consistent with the hypothesis that pressure reduces Ca2+ inflow into the presynaptic nerve terminals to affect the Ca(2+)-dependent quantal release parameters n and p.

1. The cytosolic concentration of a neurotransmitter is believed to be an important factor determining its release. The effects of ethanolamine-O-sulfate (EOS), a gamma-aminobutyric acid (GABA)-transaminase blocker, on GABAergic postsynaptic and presynaptic inhibitory neurotransmission were examined in the crayfish opener neuromuscular synapses. 2. Intracellular recordings of evoked excitatory (EPSPs) and inhibitory postsynaptic potentials (IPSPs) as well as loose macropatch clamp measurements of excitatory (EPSCs) and inhibitory postsynaptic currents (IPSCs) were used to evaluate the effects of the drug, which was applied exclusively to the nerve bundle. 3. Under normal conditions, a stimulus train to the inhibitor before the excitor stimulation elicited two phases of inhibition: 1) a large reduction in EPSP amplitude associated with a decrease in its time constant of decay (tau D) at time intervals of 0-15 ms and 2) a moderate decrease in EPSP amplitude with a small change in EPSP tau D at intervals of 15-90 ms. EOS treatment selectively increased the inhibition of phase 2. 4. The muscle membrane electrical parameters and the existing postsynaptic tonic release of GABA were not affected by the drug. 5. EOS did not alter the IPSP's parameters such as amplitude, reversal potential, and conductance. 6. Quantal analysis of single IPSCs revealed no significant changes in the statistical parameters such as quantum size (q), quantal content (m), number of active zones (n), or probability of release (p). 7. Quantal analysis of EPSCs, released after interaction with the inhibitor, did exhibit a large reduction in m without any effect on q. 8. These results demonstrate that EOS has a specific and differential effect on neural transmission in two synapses of the same axon: it increases presynaptic inhibition without significant effect on the postsynaptic inhibitory mechanism.

1. The effects of pressure on synaptic currents were examined in crayfish abdominal muscles. 2. Helium pressure (10.1 MPa) considerably decreased extracellularly-recorded excitatory junctional potentials associated with increased short-term facilitation. 3. These effects could be mimicked by a reduction of [Ca2+]o, and partially compensated by an increase in [Ca2+]o. 4. Pressure also reduced the amplitude of the extracellular nerve terminal potentials (ENTP) by up to 25%, and significantly increased synaptic delay in a [Ca2+]o-dependent manner. 5. The interaction between compression and various [Ca2+]o were analysed in terms of an existing model of transmitter release. The results were consistent with the hypothesis that high pressure decreases the maximal Ca2+ influx into nerve terminals. 6. The decreased ENTP and increased synaptic delay suggest that additional processes may be involved in pressure effects on synaptic transmission.

The effect of reactive oxygen species generated by the interaction of xanthine and xanthine oxidase on synaptic transmission was examined at the squid giant synapse and the lobster neuromuscular junction. Exposure of these synaptic regions to xanthine/xanthine oxidase produced a significant depression in evoked release, with no change in either resting membrane properties or in the action potential. Addition of catalase to the xanthine/xanthine oxidase-containing media partially blocked the synaptic depression, indicating that H2O2 contributes to the synaptic changes induced by exposure to xanthine/xanthine oxidase. H2O2 applied directly to the perfusing media also produced a decrease in synaptic efficacy. The results demonstrate that reactive oxygen species, in general, depress evoked synaptic transmission.

Radioimmunoassays for cAMP demonstrated that a beta-adrenergic agonist, isoproterenol, increased cAMP levels in isolated frog sciatic nerve. Dibutyryl cAMP (db-cAMP) and isoproterenol reduced the amplitude of the compound action potential and decreased the ability of the Xenopus sciatic nerve to follow high frequency stimulation. Similar effects of db-cAMP and a phosphodiesterase inhibitor were seen on intracellularly recorded action potentials of single lobster peripheral axons. These results suggest that cAMP can modulate the electrophysiological response properties of both myelinated and unmyelinated axons.

1. Evidence is presented that synaptic interactions within and between the statocyst and visual pathways of Hermissenda are eliminated after 0.5-4 min exposure to 20-40 mM Co2+. 2. Synaptic blockade was also produced by perfusion with low Ca2+ (5mM) plus 10-20 mM Co2+. 3. Depolarization of hair cells by impulses of type A photoreceptors remains after the same exposure to Co2+, or low Ca2+ plus Co2+. 4. The increased resistance previously observed during this depolarization of hair cells cannot be observed after exposure to Co2+. 5. The depolarization which remains after exposure to Co2+ did not change with different levels of membrane potential from -20 mV below to +10 mV above the resting level. 6. The time course of potassium accumulation, monitored by the amplitude of the type A impulse afterpotential, closely followed the time course of hair cell depolarization and also of changes in the amplitude of the hair cell afterpotential. 7. The depolarization of hair cells by type A impulses decreased with increased extracellular potassium, but was only slightly reduced by lowered extracellular potassium. 8. The amount of potassium accumulation following a type A impulse train could be estimated from the effects of changes in extracellular potassium in the perfusate on the type A impulse afterpotential. From this extimated increase of extracellular potassium it was possible to predict with some accuracy, the observed hair cell depolarization. 9. Although type A cells are not electrically coupled to ipsilateral hair cells, firing of these hair cells slightly depolarized the type A photoreceptor which excites them. 10. Strophanthidin (10-4 M) did not block the depolarization of hair cells by type A impulses. 11. The data are evidence for nonsynaptic excitation of hair cells by type A photoreceptor impulses. The data are also consistent with the interpretation that the excitation arises from potassium accumulation around the type A and hair cell axonal membranes.