Initiation, Propagation, and Termination of Epileptiform Activity in Rodent NeocortexIn VitroInvolve Distinct Mechanisms

Abstract

Waves of epileptiform activity in neocortex have three phenomenological stages: initiation, propagation, and termination. We use a well studied model of epileptiform activity in vitro to investigate directly the hypothesis that each stage is governed by an independent mechanism within the underlying cortical circuit. Using the partially disinhibited neocortical slice preparation, activity is induced and modulated using neurotransmitter receptor antagonists and is measured using both intracellular recordings and a linear array of extracellular electrodes. We find that initiation depends on both synaptic excitation and inhibition and entails a slow process of recruitment at discrete spatial locations within cortical layer 5 but not layer 2/3. Propagation depends on synaptic excitation but not inhibition and is a fast process that involves neurons across the spatial extent of the slice and in all cortical layers. Termination is modulated by synaptic excitation and inhibition. In space, termination occurs reliably at discrete locations. In time, termination is characterized by a strong depolarizing shift (block) and recovery of neurons in all cortical layers. These results suggest that the phenomenological stages of epileptiform events correspond to distinct mechanistic stages.

Local axon collaterals of area CA1 support spread of epileptiform discharges within CA1, but propagation is unidirectional

“…This was similar to the rates reported for neocortex, 0.13-0.19 m/s neocortex (Golomb and Amitai, 1997), and disinhibited hippocampal neurons cultured on a line, 0.1 m/s (Feinerman et al, 2005). Lower rates were reported in other studies of neocortex, 0.074 m/s (Pinto et al, 2005), and in subiculum, 0.04 m/s subiculum (Harris and Stewart, 2001a). These rates are all lower than the reported conduction velocity for unmyelinated CA3 axons [longitudinal association fibers: 0.39 m/s, Schaffer collaterals: 0.25 m/s (Andersen et al, 2000)].…”

“…In area CA1, the suppression of inhibition was shown to be critical for the spread of epileptiform events out of the area and into subiculum (Benini and Avoli, 2005). By contrast, Pinto et al (2005) showed that propagation in the neocortex did not depend on inhibition; inhibition determined event duration. Broadening in disinhibited preparations is contrasted with the more stable sharp wave (Buzsaki, 1986) spreading through hippocampal formation areas.…”

Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na + channels

“…This complexity and the added possibility that the effect of PA depletion on inhibitory interneurons may be markedly different from that on pyramidal neurons make it impossible to pinpoint a single mechanism. Nonetheless, axon collaterals of the layer 5 pyramidal cells we studied do provide profound excitatory input to the local circuitry, and their heightened excitability is a potent source of positive feedback (50). In this regard, it is noteworthy that some Na ϩ channel mutations associated with an inherited form of epilepsy entail an increased I NaP and are epileptogenic (51).…”

Response of traveling waves to transient inputs in neural fields

“…One particular epilepsy hypothesis, presuming there is some unhindered excitation in seizure-prone regions, has been explored using in vitro studies of disinhibited cortical slices [9]. Such paradigms have been very useful for probing how external stimuli can initiate [10] and modulate [11] traveling electrical waves.…”

“…Some of our results even speak to the critical stimuli necessary to terminate traveling waves. The stimulus, in our models, represents a short input of current from an electrode [10], rapid alteration of an external electric field [11], or a brief activation of cells with light-sensitive ion channels [37]. Parts of our theory apply to large amplitude stimuli, capable of switching parts of the network on or off.…”