George G. Somjen

Ion Regulation in the Brain: Implications for Pathophysiology

Ions in the brain are regulated independently from plasma levels by active transport across choroid plexus epithelium and cerebral capillary endothelium, assisted by astrocytes. In “resting” brain tissue, extracellular potassium ([K+]o) is lower and [H+]o is higher (i.e., pHo is lower) than elsewhere in the body. This difference probably helps to maintain the stability of cerebral function because both high [K+]o and low [H+]o enhance neuron excitability. Decrease in osmolarity enhances synaptic transmission and neuronal excitability whereas increased osmolarity has the opposite effect. Iso-osmotic low Na+ concentration also enhances voltage-dependent Ca2+ currents and synaptic transmission. Hypertonicity is the main cause of diabetic coma. In normally functioning brain tissue, the fluctuations in ion levels are limited, but intense neuronal excitation causes [K+]o to rise and [Na+]o, [Ca2+]o to fall. When excessive excitation, defective inhibition, energy failure, mechanical trauma, or blood-brain barrier defects drive ion levels beyond normal limits, positive feedback can develop as abnormal ion distributions influence neuron function, which in turn aggravates ion maldistribution. Computer simulation confirmed that elevation of [K+]o can lead to such a vicious circle and ignite seizures, spreading depression (SD), or hypoxic SD-like depolarization (anoxic depolarization).

Responses of electrical potential, potassium levels, and oxidative metabolic activity of the cerebral neocortex of cats

We measured simultaneously the oxidative metabolic activity, monitored as the tissue fluorescence attribute to intramitochondrial NADH, the extracellular potassium level with ion-selective microelectrodes, and the focal extracellular electrical potential, of one site in intact cerebral cortex of cats. When the cerebral was stimulated by trains of repeated electric pulses applied either directly to its surface or to an afferent pathway, the corrected cortical fluorescence (F-R) declined indicating oxidation of NADH, the activity of extracellular potassium [K+]o increased, and the extracellular potential (Vec) shifted in the negative direction. When mild to moderate stimuli not exceeding 10-15 sec in duration were used, a 3-fold correlation was found between these three variables. The regression of F-R over either Vec, or over log [K+]o had a positive ordinal intercept. The results are in agreement with earlier suggestions 4,24,25,43,45,46 that (a) much but not all the oxidative metabolic response of cortex to electrical stimulation is expended in restoring disturbed ion balance; and (b) that sustained shifts of potential (SP) in response to repetitive electrical stimulation are generated by glia cells depolarized by excess potassium. The magnitude of SP shifts associated with a given elevation of [k+]o are smaller in cerebral cortex than in spinal cord48,49. The correlation of F-R with [K+]o breaks down when pathologic processes of either seizure activity or spreading depression set in. During paroxysmal activity [K+]o tends to remain confined below 10-12 mM, a level observed in non-convulsing cortex as well, but oxidation of NADH progresses beyond that seen in non-convulsing cortex as well, but oxidation of NADH progresses beyond that seen in non-convulsing tissue. This observation is hard to reconcile with the suggestion that excess potassium is a factor in the generation of seizures, at least of the type observed in this study. When [K+]o levels exceeded 10-12 mM, spreading depression invariably followed at least under the unanesthetized condition in these experiments. During spreading depression [K+]o levels rose to exceed 30 mM, sometimes 80 mM. NADH was oxidized during spreading depression to a level comparable to that seen in seizures. The observations are compatible with the suggestion13 that spreading depression occurs whenever the release of potassium into extracellular fluid is overloading its clearance therefrom.

Integration in the nervous system

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The projection of jaw elevator muscle spindle afferents to fifth nerve motoneurones in the cat.

1. By spike‐triggered averaging of intracellular synaptic noise it has been shown in pentobarbitone anaesthetized cats that jaw elevator muscle spindle afferents with their cell bodies in the mid‐brain have a relatively weak monosynaptic projection to masseter and temporalis motoneurones. 2. Extending the spike‐triggered averaging method to recording extracellular excitatory field potentials it has been shown that virtually all the spindles do project monosynaptically to the motoneurone pool. It is concluded that the general weakness of the projection is due to its restriction to a small proportion of the motoneurones, possibly those concerned most with tonic postural functions. 3. The shape of individual intracellular e.p.s.p.s together with the spatial distribution of extracellular excitatory potential fields provide some evidence for a dentrically weighted distribution of the synapses. 4. Evidence is presented that both primary‐ and secondary‐type spindle afferents project monosynaptically, the secondary effects being some 71% of the strength of the primary ones.

Effects of extracellular pH on voltage-gated Na+, K+ and Ca2+ currents in isolated rat CA1 neurons.

1. The effects of extracellular H+ (pHo) in the pathophysiological range (pH 6‐8) on voltage‐gated sodium, potassium, and calcium currents were examined in acutely dissociated rat hippocampal CA1 neurons using the whole‐cell patch clamp technique. All experiments were conducted in Hepes‐buffered solutions and were performed at room temperature (21‐23 degrees C). 2. TTX‐sensitive sodium currents, evoked by both step and ramp depolarization, were reversibly depressed by moderate acidosis and enhanced slightly by alkaline exposure. Changes in current amplitude were coincident with small reversible shifts (+/‐ 3 mV) in the voltage dependence of activation. In contrast, sodium current activation and decay kinetics as well as steady‐state inactivation were unaffected by acidosis. 3. Outward potassium currents could be separated into a transient, rapidly inactivating current (IA) and a sustained, slowly inactivating component (IK). Steady‐state activation of both currents was unaffected by an increase or decrease in pHo. Similarly, IK activation and IA decay kinetics remained stable during pHo exchange. In contrast, the steady‐state inactivation (h infinity) of both potassium currents was reversibly shifted by approximately +10 mV during acid exposure, but remained unchanged during alkaline treatment. 4. Calcium currents were found to be predominantly of the high‐voltage‐activated (HVA) type, which could be carried by Ba2+ and inhibited completely by cadmium. Moderate acidosis (pH 6.9‐6.0) reversibly depressed HVA Ca2+ current amplitude and caused a positive shift in its voltage dependence. For both of these parameters, alkaline treatment (pH 8.0) had the opposite effect. The depression of HVA Ca2+ currents by low pHo was unaffected by raising the internal Hepes concentration from 10 to 50 mM in the patch pipette. A Hill plot of the effect of pH on Ca2+ current amplitude revealed a pK value (defined as the mid‐point of the titration curve) of 7.1 and a slope of 0.6. 5. The rate of Ca2+ current activation was unaffected by pHo at positive potentials, but below 0 mV the activation rate increased at low pH and decreased at high pH, becoming significant at ‐20 mV. At this membrane voltage, a second HVA current was revealed during acid exposure as the whole‐cell HVA current was depressed. Ca2+ current decay was described by two time constants, both of which were significantly reduced at pH 6.4 and slightly enhanced at pH 8.0. Steady‐state Ca2+ current inactivation reached 50% near ‐50 mV and was not affected at either pH extreme. 6. These results demonstrate that extracellular pH shifts within the pathophysiological range are capable of modulating both the conductance and gating properties of voltage‐gated ion channels in hippocampal CA1 neurons. The effects we describe are consistent with the wellknown effects of pHo on neuronal excitability and strengthen the idea that endogenous pHo shifts may help regulate cell activity in situ.

Extracellular potassium activity, intracellular and extracellular potential responses in the spinal cord.

1. Microcapillary electrode assemblies of two or three channels were used to record extracellular and intracellular potentials together with the extracellular activity of potassium ions, from essentially single locations within the substance of the decapitate spinal cord of cats. A liquid ion exchanger filled the tip of the potassium sensing microprobe. Activity was evoked by electrical stimulation of afferent peripheral nerves (ventral roots were cut). 2. Within the substance of the spinal grey matter increments of extracellular potassium activity evoked by repetitive afferent volleys were precisely correlated with magnitudes of sustained shifts of extracellular electric potential. Raising [K+]o from 3 to 4 mM was associated with a negative shift of potential of 2‐5 +/‐ 0‐5 mV, regardless of the position of the electrode in the tissue, and regardless of treatment by convulsant or depressant drugs. 3. The spatial distribution of the responses of potassium activity was mapped by the spatial distribution of the negative sustained potential shifts. 4. Depolarization shifts of potential recorded from within neuroglia cells ran parallel with changes of extracellular potassium potential. Even though the magnitude of extracellular sustained potential shifts was precisely correlated with the responses of both extracellular potassium and intracellular glial potentials, the trajectory of sustained potential shifts did not exactly mirror the two other variables. Onset and offset of sustained potential shifts were faster than those of glial potentials or of extracellular potassium. 5. The responses of the true transmembrane potential (intracellular less extracellular potential shifts) of neuroglia cells in the spinal grey matter can fully be described by the Nernst equation. 6. Membrane potentials of neurones, potentials recorded from dorsal root filaments, or from white matter, appeared unrelated to the activity of potassium ions in extracellular fluid. 7. The results are compatible with the suggestions that changes of the membrane potential of spinal neuroglia cells are fully determined by the change of the activity of extracellular potassium, and that glia cells supply most of the current which generates sustained shifts of the extracellular potential of spinal grey matter. The results are hard to reconcile with suggestions that under conditions of moderate excitation (i.e. in the absence of convulsive neuronal activity) changes of extracellular potassium would significantly influence the membrane potential of spinal neurones, or of primary afferent nerve fibres.

The effects of temperature on synaptic transmission in hippocampal tissue slices

Fully submerged rat hippocampal tissue slices were exposed to temperature changes, and the effects on CA1 pyramidal cell electrophysiology studied. Raising the temperature from 29 to 33 or 37 degrees C simultaneously increased the focal-excitatory postsynaptic potentials and decreased the population spikes. These changes were largely reversible for slices warmed to 33 degrees C, but not for slices warmed to 37 degrees C. During warming transiently increased excitatory transmission was observed; the degree of increased transmission was related to the rate of temperature rise. It is postulated that neuronal membrane hyperpolarization with warming is responsible for several of the effects seen.

Acidification of interstitial fluid in hippocampal formation caused by seizures and by spreading depression

Changes in the pH of interstitial fluid were measured with H+-selective double-barreled micropipette electrodes in fascia dentata of urethane-anesthetized rats. Paroxysmal afterdischarges provoked by repetitive stimulation of an afferent fiber tract brought in their wake acidification by 0.07 to 0.2 pH units. Spreading depression caused acidification by 0.2-0.5 pH units. Acid shifts were often preceded by transient alkalinization. Acidification is attributed to the production of CO2 and of other acid metabolites.

Chlorpromazine protects brain tissue in hypoxia by delaying spreading depression-mediated calcium influx

We have investigated the possible protective effect of chlorpromazine in hypoxia of brain tissue, using rat hippocampal slices maintained at 35-36 degrees C. The recovery of synaptic transmission along the Schaffer collaterals to the CA1 pathway after 9 min hypoxia was compared in chlorpromazine-treated and in control slices. Recovery upon reoxygenation was the exception in control slices, while it was observed in approximately 50 and 100% of slices treated with 7 and 70 microM chlorpromazine, respectively. Chlorpromazine also significantly delayed the occurrence of the hypoxia-induced spreading depression (SD). Recovery took place when SD occurred late during hypoxia, not when it occurred early. In those slices in which 7 microM chlorpromazine afforded no protection, SD occurred as early as it did in control slices. In further experiments, we deliberately induced SD during hypoxia in 70 microM-treated slices by topically applying a drop of high-K+ artificial cerebrospinal fluid (ACSF). Recovery was not observed when SD was induced early, but it was observed when it was induced near the end of the hypoxic period. Slices exposed to the same period of hypoxia in Ca2+-free ACSF recovered synaptic transmission (even without chlorpromazine treatment) despite early induction of SD. We conclude that: chlorpromazine protects brain tissue from hypoxia-induced irreversible loss of synaptic transmission; it does so by delaying the occurrence of SD, and hence shortening the time spent in the SD-induced depolarized state; and the harm done by SD in hypoxia is related to the influx of Ca2+ into neurons.

Electrogenesis of sustained potentials

Abstract The weight of evidence, as of this date, is in favor of the hypothesis of a predominantly glial generation of the SP shifts which are evoked by repetitive stimulation of afferent nerves or of fiber tracts. Unlike electrically evoked SP shifts, the SP shifts associated with spreading depression are probably generated by massive depolarization of all cells, glia as well as neurones. For SP shifts related to more physiological process, such as the contingent negative variation, the SP shifts or positive reinforcement and the related ‘consummatory potential’, the evidence is insufficient even for a tentative conclusion. SP shifts of varying intensity are associated with a proportional increase of oxidative energy turnover. During spreading depression the electron transport of the oxidative enzyme chain is accelerated well beyond the level observed in healthy cortex. The cause of spreading depression is not a shortage of the supply of oxidative energy. Dorsal root potentials do not significantly contribute to SP shifts of the spinal cord, nor do SP shifts appear to cause dorsal root potentials. There is no convincing reason at this time to suggest that under normal conditions neurones are influenced by sustained currents flowing in the extracellular medium. The more intense extracellular currents occurring during pathological conditions may possibly contribute to spreading depression and/or other types of paroxysmal activity. More quantitative data are badly needed to decide these fundamental questions. The curious immunity of the spinal cord and of the immature brain to spreading depression challenges the ingenuity of the pathophysiologist.