Partial Disinhibition Is Required for Transition of Stimulus-Induced Sharp Wave–Ripple Complexes Into Recurrent Epileptiform Discharges in Rat Hippocampal Slices

Abstract

Sharp wave-ripple complexes (SPW-Rs) in the intact rodent hippocampus are characterized by slow field potential transients superimposed by close to 200-Hz ripple oscillations. Similar events have been recorded in hippocampal slices where SPW-Rs occur spontaneously or can be induced by repeated application of high-frequency stimulation, a standard protocol for induction of long-lasting long-term potentiation. Such stimulation is reminiscent of protocols used to induce kindling epilepsy and ripple oscillations may be predictive of the epileptogenic zone in temporal lobe epilepsy. In the present study, we investigated the relation between recurrent epileptiform discharges (REDs) and SPW-Rs by studying effects of partial removal of inhibition. In particular, we compared the effects of nicotine, low-dose bicuculline methiodide (BMI), and elevated extracellular potassium concentration ([K(+)](o)) on induced SPW-Rs. We show that nicotine dose-dependently transformed SPW-Rs into REDs. This transition was associated with reduced inhibitory conductance in CA3 pyramidal cells. Similar results were obtained from slices where the GABAergic conductance was reduced by application of low concentrations of BMI (1-2 μM). In contrast, sharp waves were diminished by phenobarbital. Elevating [K(+)](o) from 3 to 8.5 mM did not transform SPW-Rs into REDs but significantly increased their incidence and amplitude. Under these conditions, the equilibrium potential for inhibition was shifted in depolarizing direction, whereas inhibitory conductance was significantly increased. Interestingly, the propensity of elevated [K(+)](o) to induce seizure-like events was reduced in slices where SPW-Rs had been induced. In conclusion, recruitment of inhibitory cells during SPW-Rs may serve as a mechanism by which hyperexcitation and eventually seizure generation might be prevented.

What Is the Clinical Relevance of In Vitro Epileptiform Activity?

“…Consistent with these observations of the interaction between manipulations that alter excitability, induction of recurrent epileptiform burst discharges by tetanic stimulation makes it more diffi cult to induce seizure-like activity using elevated K + [ 59 ]. Barbarosie and Avoli [ 7 ] observed that in the presence of the convulsant 4AP, seizure activity could be initiated following transection between CA1 and entorhinal cortex.…”

No evidence for role of extracellular choline-acetyltransferase in generation of gamma oscillations in rat hippocampal slices in vitro

“…ACh binds to both ionotropic nicotinic receptors, and metabotropic G protein-dependent muscarinic receptors. Nicotinic receptors containing a4 subunits found on hippocampal pyramidal cells show rapid desensitization (Liotta et al, 2011), while nicotinic receptors containing a7 subunits are typically expressed on parvalbumin-negative basket cells (Freund and Gulya´s, 1997). Muscarinic receptors, on the other hand, are present in different types of neurons and can be blocked by atropine, and, in case of M1 receptors, by pirenzepine (Mu¨ller and Misgeld, 1989).…”

Serotonin dependent masking of hippocampal sharp wave ripples

“…One model of seizure induction relies on increasing extracellular potassium concentrations. But rather than being pro-epileptic, the threshold for seizure induction is higher in slices in which SPW-Rs have been induced compared to naïve slices (Liotta et al, 2011).…”

“…In the initial experiments we did not block GABAergic potentials. We therefore performed a series of experiments where we applied 5 mM bicuculline after CA3 removal which was previously shown to block phasic inhibition under our experimental conditions (Liotta et al, 2011). These results are depicted in Fig.…”