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.
Epsztein
Jérôme
J
Institut de Neurobiologie de la Méditerranée, and Université de La Méditerranée, Parc scientifique de Luminy, 13273 Marseille Cedex 09, France.
Milh
Mathieu
M
Bihi
Rachid Id
RI
Jorquera
Isabel
I
Ben-Ari
Yehezkel
Y
Represa
Alfonso
A
Crépel
Valérie
V
D000818:Animals; D004569:Electroencephalography; D004594:Electrophysiology; D004827:Epilepsy / Q000209:etiology* / Q000503:physiopathology*; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D007395:Interneurons / Q000378:metabolism / Q000473:pathology; D008297:Male; D009411:Nerve Endings / Q000378:metabolism / Q000473:pathology; D009433:Neural Inhibition; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000150:complications* / Q000473:pathology; D013569:Synapses; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid