Impairment of GABA release in the hippocampus at the time of the first spontaneous seizure in the pilocarpine model of temporal lobe epilepsy.
The alterations in GABA release have not yet been systematically measured along the natural course of temporal lobe epilepsy. In this work, we analyzed GABA extracellular concentrations (using in vivo microdialysis under basal and high K(+)-evoked conditions) and loss of two GABA interneuron populations (parvalbumin and somatostatin neurons) in the ventral hippocampus at different time-points after pilocarpine-induced status epilepticus in the rat, i.e. during development and progression of epilepsy. We found that (i) during the latent period between the epileptogenic insult, status epilepticus, and the first spontaneous seizure, basal GABA outflow was reduced to about one third of control values while the number of parvalbumin-positive cells was reduced by about 50% and that of somatostatin-positive cells by about 25%; nonetheless, high K(+) stimulation increased extracellular GABA in a proportionally greater manner during latency than under control conditions; (ii) at the time of the first spontaneous seizure (i.e., when the diagnosis of epilepsy is made in humans) this increased responsiveness to stimulation disappeared, i.e. there was no longer any compensation for GABA cell loss; (iii) thereafter, this dysfunction remained constant until a late phase of the disease. These data suggest that a GABAergic hyper-responsiveness can compensate for GABA cell loss and protect from occurrence of seizures during latency, whereas impaired extracellular GABA levels can favor the occurrence of spontaneous recurrent seizures and the maintenance of an epileptic state.
Department of Medical Sciences, Section of Pharmacology, Neuroscience Center, University of Ferrara, Italy; National Institute of Neuroscience, Italy. Electronic address: marie.soukupova@unife.it.
Marie
M
Soukupová
Department of Medical Sciences, Section of Pharmacology, Neuroscience Center, University of Ferrara, Italy; National Institute of Neuroscience, Italy.
Anna
A
Binaschi
Department of Medical Sciences, Section of Pharmacology, Neuroscience Center, University of Ferrara, Italy; National Institute of Neuroscience, Italy.
Chiara
C
Falcicchia
Department of Medical Sciences, Section of Pharmacology, Neuroscience Center, University of Ferrara, Italy; National Institute of Neuroscience, Italy; Laboratory of Technologies for Advanced Therapy (LTTA), Technopole of Ferrara, Italy.
Silvia
S
Zucchini
Department of Medical Sciences, Section of Pharmacology, Neuroscience Center, University of Ferrara, Italy; National Institute of Neuroscience, Italy.
Paolo
P
Roncon
Department of Physiology and Pharmacology University of Roma "Sapienza", Italy; IRCCS San Raffaele Pisana, Roma, Italy.
Eleonora
E
Palma
Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, University of Ferrara, Italy.
Eros
E
Magri
Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, University of Ferrara, Italy.
Enrico
E
Grandi
Department of Medical Sciences, Section of Pharmacology, Neuroscience Center, University of Ferrara, Italy; National Institute of Neuroscience, Italy; Laboratory of Technologies for Advanced Therapy (LTTA), Technopole of Ferrara, Italy.
Michele
M
Simonato
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced* / Q000473:pathology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D017551:Microdialysis; D018721:Muscarinic Agonists / Q000633:toxicity*; D009474:Neurons / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D010862:Pilocarpine / Q000633:toxicity*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013004:Somatostatin / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014741:Video Recording; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018721:Muscarinic Agonists; D010320:Parvalbumins; D026941:Sodium Channel Blockers; D010862:Pilocarpine; D013779:Tetrodotoxin; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride; D002118:Calcium
GABA release; Parvalbumin; Pilocarpine; Somatostatin; Temporal lobe epilepsy