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The Journal of Neuroscience, September 15, 1998, 18(18):7543-7551
Activity-Dependent pH Shifts and Periodic Recurrence of
Spontaneous Interictal Spikes in a Model of Focal Epileptogenesis
Marco
de Curtis1,
Alfredo
Manfridi2, and
Gerardo
Biella1
1 Department of Experimental Neurophysiology, Istituto
Nazionale Neurologico, 20133 Milan, Italy and 2 Institute
of Human Physiology II, University of Milan, 20133 Milan, Italy
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- -glycyrrethinic acid (20 µM)
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.
Key words:
epileptogenesis; interictal spikes; isolated brain
preparation; periodic activity; pH; piriform cortex
Copyright © 1998 Society for Neuroscience 0270-6474/98/18187543-09$05.00/0
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