Activity-dependent pH shifts and periodic recurrence of spontaneous interictal spikes in a model of focal epileptogenesis.
The mechanisms that control the periodicity of spontaneous epileptiform cortical potentials were investigated in the in vitro isolated guinea pig brain preparation. A brief intracortical application of bicuculline in the piriform cortex induced spontaneous interictal spikes (sISs) that recurred with high periodicity (8.5 +/- 3.1 sec, mean +/- SD). Intracellular recordings from principal neurons showed that the early phase of the inter-sIS period is caused by a GABAb receptor-mediated inhibitory potential. The late component of the interspike period correlated to a slowly decaying depolarization abolished at membrane potentials positive to -32.1 +/- 5.3 mV and was not associated with membrane conductance changes. Specific pharmacological tests excluded the contribution of synaptic and intrinsic conductances to the late inter-sIS interval. Recordings with ion-sensitive electrodes demonstrated that sISs determined both a rapid increase in extracellular K+ concentration (0.5-1 mM) and an extracellular alkalinization (0.05-0.08 pH units) that slowly decayed during the inter-sIS period and returned to control values just before a subsequent sIS was generated. These observations were not congruous with the presence of a silent period, because both extracellular increase in K+ and alkalinization are commonly associated with an increase in neuronal excitability. Extracellular alkalinization could be correlated to an sIS-induced intracellular acidification, a phenomenon that reduces cell coupling by impairing gap junction function. When intracellular acidification was transiently prevented by arterial perfusion with NH4Cl (10-20 mM), spontaneous ictal-like epileptiform discharges were induced. In addition, the gap junction blockers octanol (0.2-2 mM) and 18-alpha-glycyrrethinic acid (20 microM) applied either via the arterial system or locally in the cortex completely and reversibly abolished the sIS. The results reported here suggest that the massive cell discharge associated with an sIS induce a strong inhibition, possibly secondary to a pH-dependent uncoupling of gap junctions, that regulates sIS periodicity.
de Curtis
M
M
Department of Experimental Neurophysiology, Istituto Nazionale Neurologico, 20133 Milan, Italy.
Manfridi
A
A
Biella
G
G
D000136:Acid-Base Equilibrium / Q000502:physiology*; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000287:Administration, Topical; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000209:etiology* / Q000503:physiopathology*; D005110:Extracellular Space / Q000502:physiology; D006034:Glycyrrhetinic Acid / Q000494:pharmacology; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D000442:Octanols / Q000494:pharmacology; D010507:Periodicity
D000893:Anti-Inflammatory Agents; D000442:Octanols; D000643:Ammonium Chloride; D006034:Glycyrrhetinic Acid