Subiculum network excitability is increased in a rodent model of temporal lobe epilepsy

Abstract

In this study, we used in vitro electrophysiology along with immunohistochemistry and molecular techniques to study the subiculum--a limbic structure that gates the information flow from and to the hippocampus--in pilocarpine-treated epileptic rats. Comparative data were obtained from age-matched nonepileptic controls (NEC). Subicular neurons in hippocampal-entorhinal cortex (EC) slices of epileptic rats were: (i) hyperexcitable when activated by CA1 or EC inputs; and (ii) generated spontaneous postsynaptic potentials at higher frequencies than NEC cells. Analysis of pharmacologically isolated, GABA(A) receptor-mediated inhibitory postsynaptic potentials revealed more positive reversal potentials in epileptic tissue (-67.8 +/- 6.3 mV, n = 16 vs. -74.8 +/- 3.6 mV in NEC, n = 13; P < 0.001) combined with a reduction in peak conductance (17.6 +/- 11.3 nS vs. 41.1 +/- 26.7 nS in NEC; P < 0.003). These electrophysiological data correlated in the epileptic subiculum with (i) reduced levels of mRNA expression and immunoreactivity of the neuron-specific potassium-chloride cotransporter 2; (ii) decreased number of parvalbumin-positive cells; and (iii) increased synaptophysin (a putative marker of sprouting) immunoreactivity. These findings identify an increase in network excitability within the subiculum of pilocarpine-treated, epileptic rats and point at a reduction in inhibition as an underlying mechanism.

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

“…Such a mechanism has been reported in the hippocampus and EC layers II/III (Bekenstein and Lothman, 1993;Williams et al, 1993;Sloviter, 1987;Doherty and Dingledine, 2001;Sloviter et al, 2003;Kumar and Buckmaster, 2006). Experiments performed in pilocarpine-treated rats have also demonstrated that pharmacologically isolated, GABA A receptor-mediated IPSPs have more positive reversal potentials in neurons recorded in vitro from the epileptic subiculum, peirhinal cortex and amygdala (de Guzman et al, 2006;Benini and Avoli, 2005;Benini et al, 2011); these data often correlated with reduced levels of mRNA expression and immunoreactivity of the neuron-specific cotransporter KCC2. In line with the view that altered homeostasis of intracellular [Cl − ] is associated with epileptogenesis, NKCC1 mRNA and proteins in the mouse CA1 subfiled are up-regulated up to 45 days following pilocarpine-induced status epilepticus, while KCC2 is down-regulated (Li et al, 2008).…”

“…For instance, robust periods of firing depression (presumably corresponding to IPSPs) have been recorded in electrophysiological studies performed presurgically with intracranial electrodes or extracellular unit recordings in TLE patients (Wilson and Engel, 1993;Isokawa-Akesson et al, 1989). Moreover, histochemical studies have demonstrated that some interneuron subtypes are preserved in both human and experimental animal epileptic tissue Davenport et al, 1990;Esclapez et al, 1997) even though some other subtypes are clearly decreased in number in specific limbic structures (de Guzman et al, 2006(de Guzman et al, , 2008.…”

In vitro ictogenesis and parahippocampal networks in a rodent model of temporal lobe epilepsy

“…The latter changes along with NMDA receptor upregulation have been reported in pilocarpine-treated parahippocampal areas such as the subiculum (Knopp et al, 2005;de Guzman et al, 2006), the EC (Kobayashi et al, 2003;Kumar and Buckmaster, 2006;Yang et al, 2006;de Guzman et al, 2008) and the lateral amygdala (LA) (Benini and Avoli, 2005). In addition, modified GABA A receptor signaling due to changes in K + /Cl − cotransporter has been identified in the epileptic human subiculum in vitro (Cohen et al, 2002;Wozny et al, 2003;Huberfeld et al, 2007).…”

“…de Guzman et al, 2006Guzman et al, , 2008. All efforts were made to minimize the number of animals used and their suffering.…”

“…In spite of the highly documented hyperexcitability characterizing the epileptic brain (Sloviter, 1987;Esclapez et al, 1999;Kobayashi et al, 2003;Kumar and Buckmaster, 2006;de Guzman et al, 2006de Guzman et al, , 2008, recent evidence has challenged the idea that epileptic tissue may respond to convulsant drug treatment by generating synchronous epileptiform discharges similar to those observed in control. We have previously reported that 4AP treatment can induce prolonged periods of sustained epileptiform activity in limbic brain slices obtained from pilocarpine-treated mice .…”