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G G Somjen

Publications and source records attributed to G G Somjen.

At least 19 recordsLinked to original sources
PubMed1992

Suppression of presynaptic calcium currents by hypoxia in hippocampal tissue slices.

We tested the hypothesis that suppression of inward calcium current in presynaptic terminals is the cause of failure of synaptic transmission early during cerebral hypoxia. Postsynaptic responses in CA1 zone of hippocampal tissue slices were blocked either by the combined administration of 6,7-dinitroquinoxaline-2,3-dione (DNQX) and 3-((+-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP) or by lowering extracellular calcium concentration ([Ca2+]o). Repetitive orthodromic activation of central neurons caused transient decrease of [Ca2+]o (measured by ion selective microelectrodes) in neuropil, attributable to influx of Ca2+ in presynaptic terminals. Presynaptic [Ca2+]o responses were rapidly and reversibly suppressed when oxygen was withdrawn from hippocampal tissue slices. The 'resting' baseline level of [Ca2+]o declined at first gradually, then precipitously as in spreading depression (SD). Presynaptic volleys during high frequency train stimulation were also depressed somewhat before SD began. We conclude that (1) presynaptic Ca2+ currents fail during hypoxia, perhaps because 'resting' intracellular free Ca2+ activity is increased and, in part, also because of partial failure of presynaptic impulse conduction; (2) the influx of Ca2+ into brain cells in hypoxic spreading depression is not mediated by glutamate/aspartate dependent channels.

Action Potentials↗
PubMed1992

Current source density of sustained potential shifts associated with electrographic seizures and with spreading depression in rat hippocampus.

The membrane currents responsible for the sustained potential shifts associated with electrographic seizures and with spreading depression in hippocampus were studied in the anesthetized rat. Probes incorporating 16 sensors in a straight line, spaced at 150-microns distances, were recording the potential changes with DC-coupled amplifiers in CA1 and dentate gyrus (DG) of one hemisphere. Seizures and spreading depression were provoked by repetitive stimulation of different afferent pathways. Seizures always began in DG before CA1, regardless of the pathway stimulated. Tonic seizures were associated with a sustained negative potential shift that was largest in the cell body layers. Current source density was computed from these recordings and confirmed the presence of a current sink limited to the cell body layer throughout the duration of electrographic seizures. Spreading depression was associated with a very large sink located in the layer of apical dendrites, maximal among the proximal segment of dendrites, to which the cell body layer served as a source. We conclude that seizures are associated with an inward current in neuron cell bodies, probably flowing through membrane channels of as yet no know physiological function.

Animals↗
PubMed1992

Whole-cell membrane current and membrane resistance during hypoxic spreading depression.

In rat hippocampal tissue slices we recorded extracellular potential (Vo) and whole-cell patch clamp current of CA1 pyramid cells. During hypoxic spreading depression (SD)-like depolarization, the holding current (Ih) increased sharply. Membrane 'slope' resistance (Rm) decreased to 10-67% (mean 39%) of the resting value. The SD-related membrane current (ISD) reversed near zero mV. With voltage dependent K+ and Na+ currents blocked by Cs+ and QX-314, shifts of Ih and decrease of Rm during SD were not suppressed. We conclude that hypoxic SD of CA1 pyramidal cells is associated with a large non-selective inward current through yet to be identified membrane mechanisms, which cannot fully explain the SD-related Vo shift.

Animals↗
PubMed1992

Mechanism of spreading depression: a review of recent findings and a hypothesis.

Spreading depression of Leão (SD) can be provoked by numerous nonspecific mechanical, electrical, and chemical stimuli. A similar, if not identical, phenomenon can be provoked by hypoxia. SD is characterized by drastic depolarization of neurons, severe reduction of membrane resistance, and redistribution of ions across cell membranes. Glial cells also depolarize but retain membrane resistance. Tetraethylammonium hastens the onset of hypoxic SD but reduces the sustained potential shift and K+ outflow from cells; 4-aminopyridine also accelerates SD but has no effect on the voltage shift. N-Methyl-D-aspartate receptor antagonists delay the onset of SD, while nickel and cobalt reduce the amplitude of SD-related redistribution of Ca2+. Yet, no specific blocker of SD has been found. Microdialysis of high-K+ solution in hippocampal CA1 region induces recurrent waves of SD propagating semi-independently in adjacent tissue layers, and a prolonged unstable depressed state that has not previously been described. Neither the release of K+ ions nor of glutamate is the unique agent of SD propagation. On the basis of recent findings we propose a hypothetical sequence of events that reconcile many of the previously seemingly paradoxical observations.

Animals↗
PubMed1991

Lasting neuron depression induced by high potassium and its prevention by low calcium and NMDA receptor blockade.

Spreading depression-like neuron depolarization was induced in CA1 of hippocampal tissue slices by irrigation with artificial cerebrospinal fluid containing 133.5 mM K+ for 8-40 min. Evoked responses disappeared during irrigation with high-K+ solution. Following 8-20 min irrigation orthodromic responses showed a triphasic recovery cycle: early partial return with evidence of neuron hyperexcitability, then secondary depression and finally slow partial recovery. After 30 min or more of high-K+ exposure, ortho- and antidromic responses remained severely depressed for at least 5.5 to 6.5 h. When, however, the tissue was deprived of calcium, or N-methyl-D-aspartate (NMDA) receptors were blocked by 10 microM 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), then evoked responses recovered partially after a 30- or 40-min high-K+ exposure. Post-exposure hyperexcitability was not prevented by CPP. We conclude that prolonged depolarization by elevated K+ causes irreversible neuron damage, which is triggered or accelerated by influx of calcium ions into neurons, mediated in part by NMDA receptor activation.

Animals↗
PubMed1991

Calcium, magnesium, and long-term recovery from hypoxia in hippocampal tissue slices.

Ortho- and antidromic responses recovered and remained robust for 5 h in slices exposed to transient hypoxia in low calcium, while responses remained depressed in slices made hypoxic in normal calcium. Elevating magnesium in addition to reducing calcium did not improve recovery compared to reducing calcium alone. Spreading depression-like hypoxic depolarization occurred earlier in low calcium than in control fluid. We conclude that loss of function was triggered by calcium uptake by neurons and not by cell swelling, and that activation of NMDA receptors probably played no part.

Animals↗
PubMed1991

Ion channel involvement in hypoxia-induced spreading depression in hippocampal slices.

Rat hippocampal tissue slices were made hypoxic in control medium and in medium containing the ion channel blockers tetraethylammonium (TEA), 4-aminopyridine (4-AP), or tetrodotoxin (TTX). Postsynaptic evoked potentials, extracellular DC potential Vec, and in some experiments extracellular potassium concentration [K+]o were monitored in stratum pyramidale of the CA1 region. TEA (10 mM) decreased the latency of hypoxia-induced spreading depression (SD), and reduced the amplitudes of the changes in Vec and [K+]o. 4-AP (50 microM) also decreased the latency of SD but had no effect on the Vec shift. In most slices, TTX (1 microM) increased SD latency but had no effect on the Vec shift. In some slices, TTX blocked the occurrence of SD.

4-Aminopyridine↗
PubMed1991

Osmotic-hypertensive opening of the blood-brain barrier in rats does not necessarily provide access for potassium to cerebral interstitial fluid.

The blood-brain barrier was breached in urethane anaesthetized rats by infusing hypertonic mannitol or NaCl at high rate under high pressure into one internal carotid artery. Opening of the blood-brain barrier was confirmed by staining of the perfused hemisphere by intravenous Evans Blue dye. Orthodromic-evoked potentials in CA1 region of hippocampus were transiently extinguished, and the extracellular potential in hippocampus and neocortex shifted in the positive direction during hypertonic infusion. After the hypertonic infusion, the permeability of the barrier to K+ was tested by infusing into the internal carotid artery artificial cerebrospinal fluid in which K+ replaced most of the Na+, raising the concentration of K+ in the blood plasma in the superior sagittal sinus to 13-17 mM. Extracellular potential and interstitial potassium concentration ([K+]O) in hippocampus and neocortex, and evoked potentials in hippocampus, remained unchanged during prolonged infusion of high K+, unless and until spreading depression occurred. After a wave of spreading depression, [K+]O returned to baseline in spite of continued high K+ infusion. We conclude that [K+]O in brain tissue is effectively regulated even when colloidal dye can penetrate the blood-brain barrier, but excess K+ may have entered the cerebral interstitial space in scattered patches outside the region sensed by the ion-selective microelectrodes, triggering spreading depression.

Animals↗
PubMed1990

Hypoxic failure of synaptic transmission in the isolated spinal cord, and the effects of divalent cations.

Responses evoked by stimulation of a dorsal root were recorded from ventral and dorsal roots of isolated spinal cords of infant mice. Interstitial potassium, [K+]o, and extracellular DC voltage were recorded from dorsal gray matter in some experiments. When oxygen was withdrawn, synaptically transmitted discharges (dorsal horn response, DHR, and monosynaptic ventral root reflex, VRR) began to be depressed within a minute, and were depressed to less than 30% of control amplitude in 10-15 min. Responses recovered fully if oxygen was readmitted within 45 min, but no recovery was seen after 90 min of hypoxia. The degree of the depression of VRR was as expected from the depression of the electrotonically conducted excitatory postsynaptic potential (VRepsp). Responses failed much more rapidly in spinal cords of 15-16-day-old mice, than of 9-14-day-olds. When the spinal cord was bathed in elevated [Ca2+]o or in reduced [Mg2+]o, synaptic transmission was consistently maintained for a longer period of hypoxia than in bathing fluid of normal cation content. In a sizeable minority of the trials during hypoxia an abrupt increase of [K+]o occurred, accompanied by a sudden negative shift of extracellular potential, closely resembling spreading depression (SD) of forebrain structures. Delayed post-hypoxic spontaneous activity was seen in many spinal cords. The results are compatible with the hypothesis that hypoxic failure of synaptic transmission is due, in part or whole, to blockade of inward Ca2(+)-current in presynaptic terminals. Cells in spinal gray matter can no longer be regarded as 'immune' to SD-like depolarization, but the limited conditions under which SD can occur are not yet clear.

Aging↗
PubMed1990

Spinal dorsal horn neurons in elevated extracellular calcium: cell properties and spontaneous discharges.

Recordings were made from neurons in the dorsal horn (DH), and from dorsal and ventral roots (DRs and VRs) of isolated spinal cords of infant mice. Raising calcium concentration ([Ca2+]) in the organ bath from 1.2 to 2.4 mmol/l resulted in a slight hyperpolarization, elevation of threshold current (rheobase), and augmentation of excitatory postsynaptic potentials (EPSPs). In many cells EPSPs acquired a much prolonged late phase. Orthodromic stimulation evoked in some DH neurons an action potential that had the same threshold as, and coincided in time with, the 'dorsal horn response' (DHR) recorded from DR. In spinal cords bathed in elevated [Ca2+], DR recordings showed irregularly recurring spontaneous waves, and DH neurons generated spontaneous EPSPs, often with spikes. Some neurons fired irregularly timed spontaneous action potentials that did not appear triggered by EPSPs. In less than 50% of the neurons the spontaneous EPSPs coincided in time with the spontaneous DR waves. The action potentials that appeared without EPSP were fired independently from DR activity. These observations confirm that elevation of interstitial free calcium concentration results in strong enhancement of excitatory transmission, especially of an EPSP of much extended duration. Virtually all neurons showed increased spontaneous activity in high [Ca2+], but only a minority appeared recruited into the synchronized discharges that are detectable as spontaneous waves in DR and VR recordings.

Action Potentials↗
PubMed1990

Reversible effects of hypoxia on neurons in mouse dorsal root ganglia in vitro.

Mouse dorsal root ganglia (DRG) were isolated and maintained in a tissue chamber. Membrane potential of 'A-type' neurons was recorded with intracellular electrodes. When the supply of oxygen was reduced, cells depolarized by a few mV and then maintained a stable membrane potential or partially repolarized. During depolarization the action potential was reduced in amplitude and the hyperpolarizing afterpotential was depressed. Reoxygenation within 15-88 min was followed by a brief period of hyperpolarization and then complete recovery. In about 60% of the cells, invasion of the cell soma by impulses triggered by dorsal root (DR) stimulation failed during hypoxia while action potentials could still be evoked by stimulation of the peripheral nerve and by direct intracellular stimuli. Conduction from DR into the peripheral nerve stump was unchanged indicating that the blockade of DR-evoked impulse conduction occurred at the bifurcation of the axon. Results with paired pulse stimulation indicated that impulses passing the axon bifurcation leave a long lasting (greater than or equal to 25 ms) post-spike subnormal period. In DRG cells treated with tetraethylammonium (TEA) the calcium-mediated 'shoulder' of the action potential was curtailed during oxygen withdrawal. In contrast to CNS neurons, DRG cells did not show early hypoxic hyperpolarization, nor the delayed hypoxic spreading depression-like depolarization. The findings support the suggestion that the reversible depression of synaptic potentials in the CNS during the early phase of hypoxia is caused by a combination of conduction failure at axon branch points and curtailment of voltage calcium currents of presynaptic terminals, both effects resulting in reduced transmitter output.

Action Potentials↗
PubMed1990

An NMDA-mediated component of excitatory synaptic input to dentate granule cells in 'epileptic' human hippocampus studied in vitro.

Recordings were made from human hippocampal tissue surgically removed for treatment of epilepsy. In 70% of cases, an N-methyl-D-aspartate (NMDA) receptor-mediated component was present in excitatory synaptic input to gyrus dentatus. NMDA receptors are normally present, but do not participate in low-frequency synaptic transmission, in this region of the mammalian brain. These findings suggest that recruitment of normally dormant excitatory amino acid receptors may be a feature of the epileptic brain.

2-Amino-5-phosphonovalerate↗
PubMed1990

Effects of transient forebrain ischemia in area CA1 of the gerbil hippocampus: an in vitro study.

Selective delayed post-ischemic degeneration of CA1b neurons takes place in tissue slices in vitro as it does in brain in situ. Therefore neither selectivity nor the delay of the process can be explained by vascular factors. Changes of orthodromic evoked potentials precede morphologic signs of degeneration, but antidromic activation of neurons fails pari passu with histopathologic degeneration. The marked, transient, enhancement of excitatory synaptic potentials is compatible with the idea that increased release of excitatory amino acids contributes to neuron damage. The fact that degeneration proceeds in the absence of spontaneous activity or overt electrographic seizures indicates, however, that increased excitation cannot be the sole cause of the damage. Postsynaptic excitability of neurons decreases even while synaptic potentials are enhanced. The mechanism of decreased excitability is not clear, but its development could be interpreted as a compensatory change, counteracting enhanced excitatory transmission. We confirmed that it is possible to save neurons by drug treatment administered after the ischemic insult, and demonstrated that such protection is not due to an effect on blood vessels. These findings are relevant to the proposed clinical use of NMDA receptor antagonists to prevent ischemic brain damage (Meldrum, 1985; Rothman and Olney, 1986; Choi, 1988).

Animals↗
PubMed1990

Postischemic synaptic excitation and N-methyl-D-aspartate receptor activation in gerbils.

Transient forebrain ischemia leads to the delayed degeneration of CA1b hippocampal pyramidal cells. In previous studies using the gerbil carotid occlusion model, we demonstrated that CA1b pyramidal cell degeneration is preceded by a period of enhanced excitatory transmission. Experiments with hippocampal slices prepared after 5 minutes of bilateral carotid artery occlusion show that ischemia enhances excitatory synaptic transmission and reduces pyramidal cell excitability before it abolishes synaptic function. In the present study, we tested the hypothesis that these effects require the activation of N-methyl-D-aspartate receptors during the postischemic period. Hippocampal slices were prepared 20-30 minutes after carotid occlusion, and Schaffer collateral-commissural input-output curves were constructed from recordings made every 30-60 minutes for 11-14 hours. Inclusion of the selective, reversible N-methyl-D-aspartate receptor antagonist 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid in the superfusion medium completely prevented the progressive loss of pyramidal cell excitability that normally follows this ischemic insult. This antagonist also prevented the postischemic increases in the duration and initial slope of the focally-recorded excitatory postsynaptic potential. The antagonist could still partially block the effects of transient forebrain ischemia when treatment was delayed for 4 hours. Our results confirm that the deleterious electrophysiologic changes in area CA1b depend on the continuing activation of N-methyl-D-aspartate receptors. Delayed ischemic neuronal death may result, in part, from excessive synaptic excitation during the postischemic period. However, other factors that are eliminated by preparing hippocampal slices appear to play an important role as well.

Animals↗
PubMed1990

Spreading depression-like depolarization and selective vulnerability of neurons. A brief review.

If oxygen is withdrawn from rat hippocampal slices, a spreading depression-like response occurs earlier and is of larger amplitude in the CA1 area than in the dentate gyrus. After reoxygenation, recovery of synaptic transmission correlates inversely with the time spent in spreading depression. Recovery occurs more frequently in dentate gyrus than in CA1. Chlorpromazine and the gangliosides GM1 and AGF2 promote recovery from hypoxic depression of synaptic transmission in CA1. Prevention of irreversible loss of function correlates closely with a shortening of the time spent in spreading depression. If Ca2+ is withdrawn before hypoxia, then synaptic function recovers upon restoration of oxygen and [Ca2+]o, despite prolonged spreading depression. When spreading depression lasting more than 6-9 minutes is induced in fully oxygenated slices by superfusion with high-K+ solution, then transient recovery is followed by long-lasting loss of synaptic function. In intact brain of anesthetized rats, synaptic transmission in CA1 recovers after spreading depression-like depolarization lasting more than 30 minutes, but is lost irreversibly after 60 minutes. We conclude that entry of Ca2+ into neurons caused by spreading depression-like depolarization is important in the selective vulnerability of neurons; the duration of depolarization is critical to cell survival; and in the presence of a normal blood supply, neurons resist protracted spreading depression-like depolarization.

Animals↗
PubMed1989

Spreading depression-like hypoxic depolarization in CA1 and fascia dentata of hippocampal slices: relationship to selective vulnerability.

Hippocampal tissue slices were made hypoxic for 4-10 min and then reoxygenated for 60-120 min. Postsynaptic evoked potentials were recorded and extracellular DC potential was monitored continuously in stratum (st.) pyramidale of CA1 and st. granulosum of fascia dentata (FD). In some preparations extracellular potassium ([K+]o) and calcium ([Ca2+]o) were also recorded in both regions. Postsynaptic responses disappeared sooner during hypoxia and were less likely to recover upon reoxygenation in CA1 than in FD. The CA1 region exhibited a spreading depression (SD)-like response to hypoxia more often than did FD. When both regions showed SD-like depolarization, voltage shift and elevation of [K+]o were of greater magnitude and shorter latency in CA1. The probability of posthypoxic recovery of synaptic transmission was inversely related to the time spent in the SD-like state in both CA1 and FD. We conclude that the selective vulnerability of CA1 neurons to hypoxic and ischemic damage may be due, at least in part, to the region's propensity to undergo prolonged and severe SD-like depolarization.

Action Potentials↗
PubMed1989

Spontaneous activity induced in isolated mouse spinal cord by high extracellular calcium and by low extracellular magnesium.

Spontaneous discharges were observed in recordings from dorsal and ventral roots (DRs and VRs) of hemisected mouse spinal cords in vitro when bath [Ca2+] was raised from the control level of 1.2 to 1.8 or 2.4 mmol/l, and when bath [Mg2+] was lowered resembling drug-induced 'interictal' discharges described earlier. Maximum discharge frequency was reached at 2.4 or 3.6 mmol/l [Ca2+] while at higher concentrations mean frequency diminished but mean amplitude still increased somewhat. The frequency distribution of wave amplitudes suggests recruitment of neurons by groups or assemblies. The pacemaker is located in the dorsal spinal quadrant. The GABAA receptor antagonists picrotoxin and bicuculline in low concentration blocked the spontaneous activity, indicating an obligatory GABAergic link in the pacemaker circuit. The NMDA antagonists D.L-APV and D-APV in high concentration variably depressed but did not abolish spontaneous activity. The propensity of spinal neuron assemblies for self-paced discharge may contribute to the pathologic irritability of injured spinal cords.

2-Amino-5-phosphonovalerate↗