Epileptiform synchronization in the cingulate cortex

Abstract

SUMMARYPurpose: The anterior cingulate cortex (ACC)-which plays a role in pain, emotions and behaviorcan generate epileptic seizures. To date, little is known on the neuronal mechanisms leading to epileptiform synchronization in this structure. Therefore, we investigated the role of excitatory and inhibitory synaptic transmission in epileptiform activity in this cortical area. In addition, since the ACC presents with a high density of opioid receptors, we studied the effect of opioid agonism on epileptiform synchronization in this brain region. Methods: We used field and intracellular recordings in conjunction with pharmacological manipulations to characterize the epileptiform activity generated by the rat ACC in a brain slice preparation. Results: Bath-application of the convulsant 4-aminopyridine (4AP, 50 lM) induced both brief and prolonged periods of epileptiform synchronization resembling interictal-and ictal-like discharges, respectively. Interictal events could occur more frequently before the onset of ictal activity that was contributed by N-methyl-D-aspartate (NMDA) receptors. Mu-opioid receptor activation abolished 4AP-induced ictal events and markedly reduced the occurrence of the pharmacologically isolated GABAergic synchronous potentials. Ictal discharges were replaced by interictal events during GABAergic antagonism; this GABA-independent activity was influenced by subsequent mu-opioid agonist application. Conclusions: Our results indicate that both glutamatergic and GABAergic signaling contribute to epileptiform synchronization leading to the generation of electrographic ictal events in the ACC. In addition, mu-opioid receptors appear to modulate both excitatory and inhibitory mechanisms, thus influencing epileptiform synchronization in the ACC.

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

“…This evidence has later been confirmed in hippocampus-entorhinal cortex slices (Avoli et al, 1996a) and in brain slice preparations that included the entorhinal and perirhinal cortices (de Guzman et al, 2004) (Fig. 7A), the amygdala (Benini et al, 2003), the insular cortex (Sudbury and Avoli, 2007), or the cingulate cortex (Panuccio et al, 2009). …”

“…In addition, these glutamatergic independent interictal events are abolished by GABA A receptor antagonists (Fig. 8D) as well as by the μ-opioid receptor agonist [D-ala 2 , N-Me-Phe 4 , Gly 5 -ol]-enkephalin (DAGO) (Avoli et al, 1996a,b;Sudbury and Avoli, 2007;Panuccio et al, 2009) (Fig. 10B).…”

“…Slow interictal events induced by 4AP are minimally affected by the application of NMDA receptor antagonists, and surprisingly, continue to occur in the presence of NMDA and non-NMDA glutamatergic receptor antagonists. This type of glutamatergic-independent synchronous activity can be recorded from practically any limbic structures maintained in the brain slice (Avoli et al, 1996aBenini et al, 2003;Sudbury and Avoli, 2007;Panuccio et al, 2009) as well as in the isolated guinea pig brain (Uva et al, 2009). It has also been reported that the rate of occurrence of these GABAergic spikes are not influenced by modulating metabotropic glutamate receptor activity (Salah and Perkins, 2008).…”

“…Moreover, Benardo (1997) has shown that during 4AP application neocortical interneurons generate sustained action potential firing. Finally, long-lasting depolarizations with associated firing have been reported to occur in principal cells of the neocortex (Aram et al, 1991;Avoli et al, 1994) and of the cingulate cortex (Panuccio et al, 2009) during 4AP treatment.…”

Development of multi-electrode array screening for anticonvulsants in acute rat brain slices

“…Additionally, extracellular and intracellular electrophysiological recordings from intact brain slices are important techniques for highlighting potential anti-epileptic properties (D'Antuono et al, 2007). The removal of extracellular Mg 2+ ions from bathing fluid or the addition of the potassium channel blocker 4-aminopyridine (4-AP) can induce spontaneous epileptiform activity in a variety of brain slice preparations (Kovacs et al, 2009;Panuccio et al, 2009;Perreault and Avoli, 1991). This bioelectrical activity is analogous to in vivo status epilepticus as measured by electro-encephalogram (EEG).…”