Epileptiform burst activity induced by potassium in the hippocampus and its regulation by GABA-mediated inhibition

Abstract

Intracellular and extracellular recordings were made from pyramidal neurons in hippocampal slices in order to study spontaneous paroxysmal bursting induced by raising the extracellular potassium concentration from 3.5 to 8.5 mM. Extracellular recordings from all hippocampal subfields indicated that spontaneous bursts appeared to originate in region CA3c or CA3b as judged by burst onset. Burst intensity was also greatest in regions CA3b and CA3c and became progressively less toward region CA2. Intracellular recordings indicated that in 8.5 mM potassium, large spontaneous excitatory postsynaptic potentials (EPSPs), large burst afterhyperpolarizations, and rhythmic hyperpolarizing-depolarizing waves of membrane potential were invariably present in CA3c neurons. High potassium (8.5 mM) induced a positive shift (+9 mV) in the reversal potential of GABAergic inhibitory postsynaptic potentials (IPSPs) in CA3c neurons without changing input resistance or resting potential. This resulted in a drastic reduction in amplitude of the IPSP. Reduction of IPSP amplitude occurred before the onset of spontaneous bursting and was reversible upon return to normal potassium. A new technique to quantify the relative intensity of interictal-like burst discharges is described. Pentobarbital, diazepam, and GABA uptake inhibitors, which enhance GABA-mediated synaptic inhibition, reduced the intensity of potassium-induced bursts, whereas the GABA antagonist bicuculline increased burst intensity. Diphenylhydantoin and phenobarbital, anticonvulsants that have little effect on GABAergic inhibition, were without effect on spontaneous bursts. Burst frequency was reduced by bicuculline and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol but was unaffected by other drugs. Reduction of slice temperature from 35 to 19 degrees C dramatically reduced burst intensity but did not markedly affect burst frequency. We hypothesize that high potassium induces a rise in intracellular chloride concentration, possibly by activating an inward KCl pump or by a passive Donnan effect, which results in a decreased IPSP amplitude. With inhibition suppressed, the large spontaneous EPSPs that appear in high potassium cause individual CA3c neurons to fire. A combination of synaptic and electrical interactions among CA3c cells then synchronizes discharges into interictal spike bursts.

Excitatory Actions of Endogenously Released GABA Contribute to Initiation of Ictal Epileptiform Activity in the Developing Hippocampus

“…Only brief epileptiform discharges with an interval of 2-6 sec were observed in hippocampal slices from P23-P30 rats (Fig. 5C), which is similar to what has been found in studies using slices from adult brain (Rutecki et al, 1985;Korn et al, 1987).…”

“…After washing out of isoguvacine, the ictus-like activity recovered rapidly to the control level. These results from young animals are contrary to the anticonvulsant effects of GABA A -R agonists in hippocampal slices from adult rats (Korn et al, 1987).…”

Effects of carnosine on the evoked potentials in hippocampal CA1 region

“…The observations of the direct effect of carnosine on CA1 neurons are consistent with the previously reported excitatory effects of carnosine on neuron activity in the olfactory bulb neurons in vitro (Kanaki et al, 1997) and in vivo (Gonzalez-Estrada and Freeman, 1980). However, different from the appearance of spontaneous epileptiform burst induced by the PTX in this study or by high concentration of potassium (Korn et al, 1987;Rutecki et al, 1985), carnosine did not induce any spontaneous epileptiform activity in the spontaneous field potential recordings. This may be due to the insufficient strength of disinhibition effect of carnosine; however, it may also have an alternative explanation.…”

“…These results are similar to the excitatory effect of extracellular high potassium concentration on the hippocampal neurons (Korn et al, 1987;Rutecki et al, 1985) and the effect of blockade in inhibitory synaptic input by GABAergic antagonist such as PTX (Muller and Misgeld, 1991). Since the first spike in the multiple spike evoked PSs did not increase, the enhancement of excitation was presumably induced by disinhibition of interneuron activity in the hippocampus.…”

Calcium current activated by potassium ions in voltage‐clamped rat hippocampal pyramidal neurones

“…Increased [K¤]ï often occurs in the central nervous system under pathological conditions. Arterial hypoxia, especially combined with moderately reduced arterial blood pressure, may raise [K¤]ï to levels greater than 15 mÒ (Kirshner, Blank & Myers, 1975 (Zuckermann & Glaser, 1968) and in vitro (Rutecki, Lebeda & Johnston, 1985;Korn, Giacchino, Chamberlin & Dingledine, 1987;Traynelis & Dingledine, 1988;Leschinger, Stabel, Igelmund & Heinemann, 1993). Significant elevation of [K¤]ï during epileptiform discharge was revealed both in vivo and in tissue slices, its value often exceeding 10 mÒ and maximal changes occurring in the stratum pyramidale (Fisher, Pedley, Moody & Prince, 1976;Leschinger et al 1993;Avoli, Louvel, Drapeau, Pumain & Kurcewicz, 1995).…”