Heterogeneous firing behavior during ictal-like epileptiform activity in vitro

Abstract

Seizure activity in vivo is caused by populations of neurons displaying a high degree of variability in activity pattern during the attack. The reason for this variability is not well understood. Here we show in an in vitro preparation that hippocampal CA1 pyramidal cells display four types of afterdischarge behavior during stimulus-induced ictal-like events in the presence of Cs(+) (5 mM): type I (43.7%) consisting of high-frequency firing riding on a plateau potential; type II (28.2%) consisting of low-frequency firing with no plateau potential; type III (18.3%) consisting of high-frequency firing with each action potential preceded by a transient hyperpolarization and time-locked to population activity, no plateau potential; "passive" (9.9%) typified by no afterdischarge. Type I behavior was blocked by TTX (0.2 μM) and intracellular injection of QX314 (12.5-25 mM). TTX (0.2 μM) or phenytoin (50 μM) terminated ictal-like events, suggesting that the persistent Na(+) current (I(NaP)) is pivotal for type I behavior. Type I behavior was not correlated to intrinsic bursting capability. Blockade of the M current (I(M)) with linopirdine (10 μM) increased the ratio of type I neurons to 100%, whereas enhancing I(M) with retigabine (50-100 μM) greatly reduced the epileptiform activity. These results suggest an important role of I(M) in determining afterdischarge behavior through control of I(NaP) expression. We propose that type I neurons act as pacemakers, which, through synchronization, leads to recruitment of type III neurons. Together, they provide the "critical mass" necessary for ictogenesis to become regenerative.