Effects of applied currents on spontaneous epileptiform activity induced by low calcium in the rat hippocampus

doi:10.1016/S0006-8993(98)00723-9

Brain Research

Volume 806, Issue 2, 28 September 1998, Pages 186-195

https://doi.org/10.1016/S0006-8993(98)00723-9 Get rights and content

Abstract

It is known that both applied and endogenous electrical fields can modulate neuronal activity. In this study, we have demonstrated that anodic current injections can inhibit spontaneous epileptiform events in the absence of synaptic transmission. Activity was induced with low-Ca²⁺ (0.2 mM) artificial cerebrospinal fluid (ACSF) and detected with a voltage threshold detector. At the onset of an event, a current was injected into the stratum pyramidale via a tungsten electrode positioned within 150 μm of the recording site. Data was recorded with a glass pipette electrode. The results show that spontaneous epileptiform activity can be fully suppressed by subthreshold anodic currents with an average amplitude of 3.9 μA and a minimum amplitude of 1 μA. In addition, we observed that some events could be blocked by current pulses with shorter durations than the duration of the event itself. The possibility that increased tissue resistance could contribute to the efficacy of the currents was tested by measuring the step-potential increase evoked by anodic current injections. The data show a significant increase in the amplitude of the evoked potential after introduction of a low-Ca²⁺ medium, suggesting that tissue resistance is increasing. These results indicate that low-amplitude, subthreshold current pulses are sufficient to block epileptiform activity in a low-Ca²⁺ environment. The increased tissue resistance induced by sustained exposure to a low-Ca²⁺ medium could contribute to the low current amplitudes required to block the epileptiform events.

Introduction

It is well established that electrical fields play a significant role in the modulation of neuronal activity 21, 28, 31, 33, 35, 36. Exogenous fields can modify neuronal firing patterns in cortex, retina and hippocampus 7, 11, 17, 18. In the hippocampus, applied fields and currents have been shown to influence the normal neuronal activity of both pyramidal [4]and granule cells 17, 28. The degree to which the fields could modulate the activity of the neurons was dependent on the orientation and polarity of the fields with respect to the neuronal dendrites. Applied electrical fields can also affect abnormal neuronal activity. Subthreshold anodic currents applied with an extracellular monopolar electrode can suppress interictal-like epileptiform activity induced with penicillin [20]or elevated potassium [25]. Transmembrane recordings have shown that the mechanism of suppression involves a net hyperpolarization of the affected somatic neuronal membranes.

If electrical fields have such an effect on neuronal activity under conditions of normal synaptic transmission, one would expect that their significance would be even more evident in the absence of synaptic activity. Lowering [Ca²⁺]_o is known to effectively block chemical synaptic transmission in brain slice preparations [19]. Increased neuronal activity has been known to induce low Ca²⁺ levels in brain tissue. Experiments performed in vitro and in vivo revealed that local Ca²⁺ levels can decrease to concentrations as low as 0.2–0.6 mM during sustained spiking activity 13, 27, 22, 23, 26, 34. Furthermore, lowering [Ca²⁺]_o in brain tissue preparations will induce paroxysmal events that closely approximate epileptiform activity 2, 12, 29, 32, 38. These events are characterized extracellularly as prolonged negative potential shifts, which are often superimposed by high frequency population spikes. The population spikes are dependent upon the synchronized firing of large numbers of pyramidal neurons, which reveals the importance of field effects in neuronal synchronization 17, 18, 32. Because this synchronization is so dependent upon field effects and not synaptic connectivity, it is expected that applied currents would be highly effective in modulating ictal events induced with low [Ca²⁺]_o.

In particular, we tested the hypotheses that (1) applied current pulses can inhibit epileptiform activity induced by low-calcium solution and (2) the current amplitudes required for total inhibition are lower than those required to block penicillin or high potassium solutions. These hypotheses are relevant to the understanding of the interaction between electric fields and neuronal activity and to the control of abnormal neuronal activity by applied electric fields.

Section snippets

Materials and methods

All experiments were performed in hippocampal slices prepared from Sprague–Dawley rats (150–250 g). The animals were anesthetized with ethyl ether and decapitated. The brain was removed and placed immediately in ice-cold artificial cerebrospinal fluid (ACSF) with the following composition (in mM): NaCl, 124; KCl, 3.75; KH₂PO₄, 1.25; CaCl₂, 2; MgSO₄, 2; NaHCO₃, 26; dextrose, 10. Hippocampal slices (400-μm thick) were prepared on a McIlwain tissue chopper (Stoelting, Chicago, IL) and transferred

Results

Recurrent ictal-like activity was displayed in all 27 slices tested following a 1-h period of incubation in low-Ca²⁺ ACSF. This activity was characterized by a slow negative potential shift occasionally accompanied with population bursts (Fig. 2A). In 27% of the slices, the ictal events would sometimes exhibit multiple shift-peaks (Fig. 2C). The amplitude of a potential shift ranged from 1–5.4 mV, with a mean (±S.D.) amplitude of 2.66 (±1.03) mV as measured from the field baseline to the event

Discussion

The results of this study show that applied low-amplitude, subthreshold anodic currents can suppress spontaneous epileptiform activity in the absence of chemical synaptic transmission. The ictal events induced with low-Ca²⁺ ACSF were similar in character to those previously reported 2, 12, 21, 29, 31, 38. Non-excitatory subthreshold currents delivered to the somatic layer via a monopolar electrode caused a marked decrease in the amplitude of ictal events (Fig. 4). Interestingly, our data

Conclusions

Epileptiform activity induced by low [Ca²⁺]_o can be completely suppressed with anodic current injections lower than those required to block penicillin or K⁺-induced epileptiform activity. The current amplitudes required for blocking are subthreshold and do not excite the neural tissue. Ictal events can be blocked by current pulses with durations significantly shorter than the duration of the event. The greater efficacy of blocking currents in a low-Ca²⁺ environment may be due to increased

Acknowledgements

This work was supported by an NSF grant no. IBN 93-19599 and a Whitaker development award to the Department of Biomedical Engineering.

References (38)

R.H. Ashley
External calcium, intrasynaptosomal free calcium and neurotransmitter release
Biochim. Biophys. Acta
(1986)
H. Baran et al.
Effect of mannitol treatment on brain neurotransmitter markers in kainic acid-induced epilepsy
Neuroscience
(1987)
S.M. Bawin et al.
Comparison between the effects of extracellular direct and sinusoidal currents on excitability in hippocampal slices
Brain Res.
(1986)
D. Denney et al.
The effects of applied polarization on evoked electro-cortical waves in the cat
Electroencephalogr. Clin. Neurophysiol.
(1962)
F.E. Dudek et al.
Osmolality-induced changes in extracellular volume alter epileptiform bursts independent of chemical synapses in the rat: importance of non-synaptic mechanisms in hippocampal epileptogenesis
Neurosci. Lett.
(1990)
D. Durand
Electrical stimulation can inhibit synchronized neuronal activity
Brain Res.
(1986)
H. Kayyali et al.
Effects of applied currents on epileptiform bursts in vitro
Exp. Neurol.
(1991)
M. Nakagawa et al.
Suppression of spontaneous epileptiform activity with applied currents
Brain Res.
(1991)
R. Pumain et al.
Chemical synaptic transmission is not necessary for epileptic seizures to persist in the baboon Papio papio
Exp. Neurol.
(1985)
R.W. Snow et al.
Electrical fields directly contribute to action potential sychronization during convulsant-induced epileptiform bursts
Brain Res.
(1984)

R.W. Snow et al.

Synchronous epileptiform bursts without chemical transmission in CA2, CA3 and dentate areas of the hippocampus

Brain Res.

(1984)

R.W. Snow et al.

Evidence for neuronal interactions by electrical field effects in the CA3 and dentate regions of rat hippocampal slices

Brain Res.

(1986)

M. Avoli et al.

Epileptiform activity induced by low extracellular magnesium in the human cortex maintained in vitro

Ann. Neurol.

(1991)

D.M. Bers et al.

Calcium at the surface of cardiac plasma membrane vesicles: cation binding, surface charge screening, and Na–Ca exchange

J. Membr. Biol.

(1985)

J.S. Darrigo

Screening of membrane surface charges by divalent cations: an atomic representation

Am. J. Physiol.

(1978)

D. Durand et al.

Desynchronization of epileptiform activity by extracellular current pulses in rat hippocampal slices

J. Physiol.

(1994)

D.S. Faber et al.

Electrical field effects: their relevance in central neural networks

Physiol. Rev.

(1989)

H.L. Haas et al.

Low-calcium field burst discharges of CA1 pyramidal neurones in rat hippocampal slices

J. Physiol.

(1984)

U. Heinemann et al.

Extracellular free calcium and potassium during paroxysmal activity in the cerebral cortex of the rat

Exp. Brain Res.

(1977)

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Research reportEffects of applied currents on spontaneous epileptiform activity induced by low calcium in the rat hippocampus

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Conclusions

Acknowledgements

Biochim. Biophys. Acta

Neuroscience

Brain Res.

Electroencephalogr. Clin. Neurophysiol.

Neurosci. Lett.

Brain Res.

Exp. Neurol.

Brain Res.

Exp. Neurol.

Brain Res.

Brain Res.

Brain Res.

Epileptiform activity induced by low extracellular magnesium in the human cortex maintained in vitro

Ann. Neurol.

Calcium at the surface of cardiac plasma membrane vesicles: cation binding, surface charge screening, and Na–Ca exchange

J. Membr. Biol.

Screening of membrane surface charges by divalent cations: an atomic representation

Am. J. Physiol.

Desynchronization of epileptiform activity by extracellular current pulses in rat hippocampal slices

J. Physiol.

Electrical field effects: their relevance in central neural networks

Physiol. Rev.

Low-calcium field burst discharges of CA1 pyramidal neurones in rat hippocampal slices

J. Physiol.

Extracellular free calcium and potassium during paroxysmal activity in the cerebral cortex of the rat

Exp. Brain Res.

Research report
Effects of applied currents on spontaneous epileptiform activity induced by low calcium in the rat hippocampus