Ongoing epileptiform activity in the post-ischemic hippocampus is associated with a permanent shift of the excitatory-inhibitory synaptic balance in CA3 pyramidal neurons.

Ischemic strokes are often associated with late-onset epilepsy, but the underlying mechanisms are poorly understood. In the hippocampus, which is one of the regions most sensitive to ischemic challenge, global ischemia induces a complete loss of CA1 pyramidal neurons, whereas the resistant CA3 pyramidal neurons display a long-term hyperexcitability several months after the insult. The mechanisms of this long-term hyperexcitability remain unknown despite its clinical implication. Using chronic in vivo EEG recordings and in vitro field recordings in slices, we now report spontaneous interictal epileptiform discharges in the CA3 area of the hippocampus from post-ischemic rats several months after the insult. Whole-cell recordings from CA3 pyramidal neurons, revealed a permanent reduction in the frequency of spontaneous and miniature GABAergic IPSCs and a parallel increase in the frequency of spontaneous and miniature glutamatergic postsynaptic currents. Global ischemia also induced a dramatic loss of GABAergic interneurons and terminals together with an increase in glutamatergic terminals in the CA3 area of the hippocampus. Altogether, our results show a morpho-functional reorganization in the CA3 network several months after global ischemia, resulting in a net shift in the excitatory-inhibitory balance toward excitation that may constitute a substrate for the generation of epileptiform discharges in the post-ischemic hippocampus.

The role of extracellular potassium in the epileptogenic transformation of recurrent GABAergic inhibition.

PURPOSE: Epileptiform burst-firing can occur in hippocampal area CA1 where recurrent excitation is relatively weak and recurrent inhibition strong. Recent observations suggest that recurrent inhibition can transform into recurrent excitation because of collapse of the chloride gradient. Here we assess the role of potassium in this epileptogenic transformation. METHODS: Extracellular field potential recordings, combined with either intracellular recordings from pyramidal neurons or extracellular potassium concentration recordings, were made in vitro from isolated CA1 minislices cut from the rat hippocampus and in vivo from area CA1 in urethane-anesthetized rats. Burst responses were evoked by 5-Hz alveus stimulation. RESULTS: The 5-Hz alveus stimulation in vitro caused a transient period of burst responses that was associated with a transient increase in synaptic input in stratum oriens and a transient shift of the reversal potential of the synaptic potential. These changes were related to the transient increase in extracellular potassium concentration in stratum oriens. Observations in vivo confirmed the relation between bursting and extracellular potassium concentration in stratum oriens. CONCLUSIONS: Use-dependent increase of extracellular potassium concentration in stratum oriens facilitates the collapse of the chloride gradient in the basal dendrites and transforms gamma-aminobutyric acid (GABA)ergic inhibition into GABAergic excitation, giving rise to burst firing. Improvement of intracellular chloride homeostasis or extracellular potassium homeostasis could reduce epileptogenicity.