Excessive neuronal synchronization is presumably involved in epileptiform synchronization. However, the respective roles played by interneurons (GABAergic) and principal (glutamatergic) cells during interictal and ictal discharges remain unclear. Here, we employed tetrode wire recordings to establish the involvement of these two cell types in 4-aminopyridine-induced interictal- and low-voltage fast (LVF) onset ictal-like discharges in the rat entorhinal cortex in an in vitro slice preparation. We recorded a total of 90 single units (69 putative interneurons, 17 putative principal and 4 unclassified cells) from 36 slices, and found that: (i) interneurons (66.7%) were more likely to fire during interictal discharges than principal cells (35.3%); (ii) interneuron activity increased shortly before LVF ictal onset, whereas principal cell activity did not change; (iii) interneurons and principal cells fired at high rates throughout the tonic phase of the ictal discharge; however, (iv) only interneurons showed phase-locked relationship with LVF activity at 5-15Hz during the tonic phase. Finally, the association of interneuron firing with interictal discharges was maintained during blockade of ionotropic glutamatergic transmission. Our findings demonstrate the prominent involvement of interneurons in interictal discharge generation and in the transition to LVF ictal activity in this in vitro model of epileptiform synchronization.
Abstract4-Aminopyridine (4AP, 50 μM) induces interictal-and ictal-like discharges in brain slices including parahippocampal areas such as the entorhinal cortex (EC) but the relation between these two types of epileptiform activity remains undifined. Here, by employing field potential recordings in rat EC slices during 4AP application, we found that: (i) interictal events have a wide range of duration (0.4-3.3 s) and interval of occurrence (1.4-84 s); (ii) ictal discharges are either preceded by an isolated "slow" interictal discharge (ISID; duration=1.5±0.1 s, interval of occurrence=33.8±1.8 s) or suddenly initiate from a pattern of frequent polispike interictal discharge (FPID; duration=0.8±0.1 s; interval of occurrence=2.7±0.2 s); and (iii) ISID-triggered ictal events have longer duration (116±7.3 s) and interval of occurrence (425.8±42.3 s) than those initiating suddenly during FPID (58.3±7.8 s and 202.1±21.8 s, respectively). Glutamatergic receptor antagonists abolished ictal discharges in all experiments, markedly reduced FPIDs but did not influence ISIDs. We also discovered that high-frequency oscillations (HFOs, 80-500 Hz) occur more frequently during ISIDs as compared to FPIDs, and mainly coincide with the onset of ISID-triggered ictal discharges. These findings indicate that interictal events may define ictal onset features resembling those seen in vivo in low-voltage fast activity onset seizures. We propose a similar condition to occur in vivo in temporal lobe epileptic patients and animal models.
Allotetrahydrodeoxycorticosterone (THDOC) belongs to a class of pregnane neurosteroidal compounds that enhance brain inhibition by interacting directly with GABA A signaling, mainly through an increase in tonic inhibitory current. Here, we addressed the role of THDOC in the modulation of interictal-and ictal-like activity and associated high-frequency oscillations (HFOs, 80-500 Hz; ripples: 80-200 Hz, fast ripples: 250-500 Hz) recorded in vitro in the rat piriform cortex, a highly excitable brain structure that is implicated in seizure generation and maintenance. We found that THDOC: (i) increased the duration of interictal discharges in the anterior piriform cortex while decreasing ictal discharge duration in both anterior and posterior piriform cortices; (ii) reduced the occurrence of HFOs associated to both interictal and ictal discharges; and (iii) prolonged the duration of 4-aminopyridine-induced, glutamatergic independent synchronous field potentials that are known to mainly result from the activation of GABA A receptors. Our results indicate that THDOC can modulate epileptiform synchronization in the piriform cortex presumably by potentiating GABA A receptor-mediated signaling. This evidence supports the view that neurosteroids regulate neuronal excitability and thus control the occurrence of seizures.
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