Divergent paths to seizure‐like events

Abstract

Much debate exists about how the brain transitions into an epileptic seizure. One source of confusion is that there are likely to be critical differences between experimental seizure models. To address this, we have compared the evolving activity patterns in two widely used in vitro models of epileptic discharges. Brain slices from young adult mice were prepared in the same way and bathed either in 0 Mg2+ or 100 µmol/L 4AP artificial cerebrospinal fluid. We have found that while local field potential recordings of epileptiform discharges in the two models appear broadly similar, patch‐clamp analysis reveals an important difference in the relative degree of glutamatergic involvement. 4AP affects parvalbumin‐expressing interneurons more than other cortical populations, destabilizing their resting state and inducing spontaneous bursting behavior. Consequently, the most prominent pattern of transient discharge (“interictal event”) in this model is almost purely GABAergic, although the transition to seizure‐like events (SLEs) involves pyramidal recruitment. In contrast, interictal discharges in 0 Mg2+ are only maintained by a very large glutamatergic component that also involves transient discharges of the interneurons. Seizure‐like events in 0 Mg2+ have significantly higher power in the high gamma frequency band (60–120Hz) than these events do in 4AP, and are greatly delayed in onset by diazepam, unlike 4AP events. We, therefore, conclude that the 0 Mg2+ and 4AP models display fundamentally different levels of glutamatergic drive, demonstrating how ostensibly similar pathological discharges can arise from different sources. We contend that similar interpretative issues will also be relevant to clinical practice.

Short-Term Epileptiform Activity Potentiates Excitatory Synapses but Does Not Affect Intrinsic Membrane Properties of Pyramidal Neurons in the Rat Hippocampus In Vitro

“…In this study, we found no significant effect of epileptiform activity on the passive membrane properties or firing properties of CA1 hippocampal neurons, although some studies have shown such changes. For example, 4-AP-induced epileptiform activity in the neocortex increased input resistance of parvalbumin-expressing neurons and reduced the action potential threshold for parvalbumin-expressing and pyramidal neurons both [43]. Apart from the 4-AP model, an increase in input resistance has been observed in the CA1 neurons of genetically epilepsy-prone rats [44], kindled rats [45], and in the pentylenetetrazole model [17].…”

Short-term Epileptiform Activity Potentiates Excitatory Synapses but does not Affect Intrinsic Membrane Properties of Pyramidal Neurons in the Rat Hippocampus <em>in Vitro</em>

“…In this study, we found no significant effect of epileptiform activity on the passive membrane properties or firing properties of CA1 hippocampal neurons, although some studies have shown such changes. For example, 4-AP-induced epileptiform activity in the neocortex increased input resistance of parvalbumin-expressing neurons and reduced the action potential threshold for parvalbumin-expressing and pyramidal neurons both [42]. Apart from the 4-AP model, an increase in input resistance has been observed in the CA1 neurons of genetically epilepsy-prone rats [43], kindled rats [44], and in the pentylenetetrazole model [17].…”

Propagating Activity in Neocortex, Mediated by Gap Junctions and Modulated by Extracellular Potassium

“…Previously, several groups have demonstrated the coordination of interneuronal activation across single gap junctions (Galarreta and Hestrin, 1999;Gibson et al, 1999), but for more extensive propagation within cortical networks, gap junction-facilitated propagation over extended distances has only been demonstrated using pharmacological manipulation, bathing tissue in 4-AP (Szente et al, 2002;Gajda et al, 2003;Gigout et al, 2006a). This pharmacological manipulation, while of interest, does represent a rather extreme disruption of neocortical interneuron behavior (Codadu et al, 2019a). Of particular relevance to the present study is that 4-AP makes neurons more electrotonically compact, by blocking a large component of K 1 conductance, and will thus naturally facilitate electrotonic propagation.…”

“…Since 4-AP has a disproportionately large effect on the population of parvalbumin-expressing interneurons (Codadu et al, 2019a), we also chose to study the effect of raised [K 1 ] o in this same population. Electrical coupling between this population of interneurons is well established (Galarreta and Hestrin, 1999;Gibson et al, 1999), but coupling has also been described for other populations of cortical interneurons (Galarreta and Hestrin, 2001;Hestrin and Galarreta, 2005), and our findings are likely to generalize to these interneuronal populations too.…”