Initiation of network bursts by Ca2+-dependent intrinsic bursting in the rat pilocarpine model of temporal lobe epilepsy.
Chronically epileptic rats, produced by prior injection of pilocarpine, were used to investigate whether changes in intrinsic neuronal excitability may contribute to the epileptogenicity of the hippocampus in experimental temporal lobe epilepsy (TLE). Paired extra-/intracellular electrophysiological recordings were made in the CA1 pyramidal layer in acute hippocampal slices prepared from control and epileptic rats and perfused with artificial cerebrospinal fluid (ACSF). Whereas orthodromic activation of CA1 neurons evoked only a single, stimulus-graded population spike in control slices, it produced an all-or-none burst of population spikes in epileptic slices. The intrinsic firing patterns of CA1 pyramidal cells were determined by intrasomatic positive current injection. In control slices, the vast majority (97%) of the neurons were regular firing cells. In epileptic slices, only 53% the pyramidal cells fired in a regular mode. The remaining 47% of the pyramidal cells were intrinsic bursters. These neurons generated high-frequency bursts of three to six spikes in response to threshold depolarizations. A subgroup of these neurons (10.1% of all cells) also burst fired spontaneously even after suppression of synaptic activity. In epileptic slices, burst firing in most cases (ca 70%) was completely blocked by adding the Ca2+ channel blocker Ni2+ (1 mM) to, or removing Ca2+ from, the ACSF, but not by intracellular application of the Ca2+ chelater 1,2-bis(o-aminophenoxy)ethane-N,N,N ',N '-tetra-acetic acid (BAPTA), suggesting it was driven by a Ca2+ current. Spontaneously recurring population bursts were observed in a subset of epileptic slices. They were abolished by adding 2 M 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) to the ACSF, indicating that synaptic excitation is critical for the generation of these events. All sampled pyramidal cells fired repetitively during each population burst. The firing of spontaneously active bursters anteceded the population discharge, whereas most other pyramidal cells began to fire conjointly with the first population spike. Thus, spontaneous bursters are likely to be the initiators of spontaneous population bursts in epileptic slices. The dramatic up-regulation of intrinsic bursting in CA1 pyramidal cells, particularly the de novo appearance of Ca2+-dependent bursting, may contribute to the epileptogenicity of the hippocampus in the pilocarpine model of TLE. These findings have important implications for the pharmacological treatment of medically refractory human TLE.
Department of Physiology, Institute of Medical Sciences, Hebrew University-Hadassah Faculty of Medicine, Jerusalem 91120, Israel.
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D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D004594:Electrophysiology; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009532:Nickel / Q000494:pharmacology; D010862:Pilocarpine; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002614:Chelating Agents; D018691:Excitatory Amino Acid Antagonists; D010862:Pilocarpine; D004533:Egtazic Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D009532:Nickel; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium