Nonsynaptic epileptogenesis in the mammalian hippocampus in vitro. I. Development of seizurelike activity in low extracellular calcium

A. Konnerth, U. Heinemann, Y. Yaari

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Abstract

1. Epileptiform activity induced in rat hippocampal slices by lowering extracellular Ca2+ concentration ([Ca2+]0) was studied with extracellular and intracellular recordings. 2. Perfusing the slices with low Ca2+ (≤0.2 mM) or EGTA-containing solutions blocked the synaptic responses of hippocampal pyramidal cells (HPCs). Despite the block, spontaneous paroxysms, termed seizurelike events (SLEs), appeared in the CA1 area and then recurred regularly at a stable frequency. Transient hypoxia accelerated their development and increased their frequency. When [Ca2+]0 was raised in a stepwise manner, the SLEs disappeared at 0.3 mM. 3. With extracellular recording from the CA1 stratum pyramidale, a SLE was characterized by a large negative shift in the field potential, which lasted for several seconds. During this period a large population of CA1 neurons discharged intensely and often in synchrony, as concluded from the frequent appearance of population spikes. Synchronization, however, was not a necessary precursor for the development of paroxysmal activity, but seemed to be the end result of massive neuronal excitation. 4. The cellular counterpart of a SLE, as revealed by intracellular recording from HPCs in the discharge zone of the paroxysms, was a long-lasting depolarization shift (LDS) of up to 20 mV. This was accompanied by accelerated firing of the neuron. A prolonged afterhyperpolarization succeeded each LDS and arrested cell firing. Brief (~50 ms) bursts were commonly observed before LDS onset. 5. Single electrical stimuli applied focally to the stratum pyramidale or alveus evoked parxysms identical to the spontaneous SLEs, provided they surpassed a critical threshold intensity. Subthreshold stimuli elicited only small local responses, whereas stimuli of varied suprathreshold intensities evoked the same maximal SLEs. Thus the buildup of a SLE is an all or nothing or a regenerative process, which mobilizes the majority, if not all, of the local neuronal population. 6. Each SLE was followed by absolute and relative refractory periods during which focal stimulation was, respectively, ineffective and less effective in evoking a maximal SLE. 7. In most slices the spontaneous SLEs commenced at a 'focus' located in the CA1a subarea (near the subiculum). SLEs evoked by focal stimulation arose near the stimulating electrode. From their site of origin the paroxysmal discharges spread transversely through the entire CA1 area at a mean velocity of 1.74 mm/s. Consequently, the discharge zone of a SLE could encompass for several seconds the entire CA1 area. 8. We conclude that the hippocampal CA1 area is capable of generating and sustaining maximal seizure activity in the absence of chemical synaptic transmission. This is attributed to the development of strong positive feedback in the neuronal network through nonsynaptic excitatory interactions, which are not restrained by the Ca2+0-dependent inhibitory and stabilizing mechanisms operating in a normal ionic microenvironment. We propose that the accumulation and spatial dispersion of K+ in the CA1 interstitium plays a primary role in this process. The possible contribution of this and other nonsynaptic mechanisms to epileptogenesis in vivo is briefly appraised.

Original languageEnglish
Pages (from-to)409-423
Number of pages15
JournalJournal of Neurophysiology
Volume56
Issue number2
DOIs
StatePublished - 1986
Externally publishedYes

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