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