Synaptic Conductances during Interictal Discharges in Pyramidal Neurons of Rat Entorhinal Cortex

Abstract

In epilepsy, the balance of excitation and inhibition underlying the basis of neural network activity shifts, resulting in neuronal network hyperexcitability and recurrent seizure-associated discharges. Mechanisms involved in ictal and interictal events are not fully understood, in particular, because of controversial data regarding the dynamics of excitatory and inhibitory synaptic conductances. In the present study, we estimated AMPAR-, NMDAR-, and GABAA R-mediated conductances during two distinct types of interictal discharge (IID) in pyramidal neurons of rat entorhinal cortex in cortico-hippocampal slices. Repetitively emerging seizure-like events and IIDs were recorded in high extracellular potassium, 4-aminopyridine, and reduced magnesium-containing solution. An original procedure for estimating synaptic conductance during IIDs was based on the differences among the current-voltage characteristics of the synaptic components. The synaptic conductance dynamics obtained revealed that the first type of IID is determined by activity of GABAA R channels with depolarized reversal potential. The second type of IID is determined by the interplay between excitation and inhibition, with early AMPAR and prolonged depolarized GABAA R and NMDAR-mediated components. The study then validated the contribution of these components to IIDs by intracellular pharmacological isolation. These data provide new insights into the mechanisms of seizures generation, development, and cessation.

Alterations in Properties of Glutamatergic Transmission in the Temporal Cortex and Hippocampus Following Pilocarpine-Induced Acute Seizures in Wistar Rats

“…We used a linear function for AMPAR-mediated current and the Boltzmann function (Jahr and Stevens, 1990 ; Harnett et al, 2015 ) for NMDAR-mediated current. The main difference of this approach from the one utilized in our previous study (Amakhin et al, 2016 ) is that reference I-V relationship for NMDAR-mediated current ( f NMDA ( U ) in Equations (1) and (2) was not pre-recorded in a separate set of experiments but was obtained for every recorded cell individually, thus allowing us to account for slight variations of individual shape of I-V relationships in order to perform a more accurate estimation of synaptic conductances. I-V curves for isolated NMDAR-mediated currents were obtained in presence of inhibitors of GABAA (bicuculline) and AMPA (DNQX) receptors.…”

“…To assess the relative impacts of AMPA and NMDA receptors during evoked response in each neuron, we implemented the mathematical approach described in our previous study (Amakhin et al, 2016 ).…”

Computational model of interictal discharges triggered by interneurons

“…Certain kind of interictal and preictal discharges are based on the recurrent interactions of only excitatory neurons [ 2 ], [ 10 ] whereas the mechanisms of other discharges have suggested that interneurons are strongly involved [ 11 ], [ 10 ], [ 4 ], [ 12 ], [ 13 ]. Using 4-aminopyridine (4-AP) in vitro epilepsy model [ 14 ], we distinguished two basic types of IIDs: IID1s, which are mediated by GABA, and IID2s, which are mediated by both GABA and glutamate. The depolarizing effect of GABA may cause the generation of epileptiform events.…”

“…It is known that some convulsants trigger an intense firing of interneurons, which enhances GABA release [ 15 ] increases intracellular chloride concentration and may switch GABA responses to depolarization [ 16 ], [ 17 ], [ 18 ], [ 13 ]. In our previous work, a synchronous interneuronal activity with IIDs has been described, that evoked by using 4-AP, high potassium in vitro model [ 14 ]. Similar events were referred to as GABA-mediated, slow interictal potentials by [ 19 ].…”

“…The proposed mathematical model is grounded on recent whole-cell patch-clamp recordings in combined hippocampal-entorhinal cortex slices with high potassium/low magnesium concentrations and 50 μ M 4-AP in an extracellular solution [ 14 ], which were analyzed by means of synaptic conductance estimations. According to the findings, there are two different types of IIDs.…”