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.
Highlights
A great many in vitro and in vivo studies have focused on revealing the mechanisms underlying seizures and epilepsy and their treatments, but seizures in many patients with mesial temporal lobe epilepsy remain poorly controlled by antiepileptic drugs (Téllez-Zenteno and HernándezRonquillo, 2012)
We found that the frequency of the inhibitory postsynaptic currents (IPSCs) increased from 1.1 ± 0.2 Hz at the beginning of the registration to 5.1 ± 0.2 Hz (n = 21, p < 0.05, Wilcoxon signed rank test (W-test)) prior to the first synchronized event, while the frequency of excitatory postsynaptic currents (EPSCs) remained the same (0.12 ± 0.04 vs. 0.5 ± 0.2 Hz, n = 21, p > 0.05, W-test)
These data demonstrate that our measurement technique for various synaptic conductances is reasonably accurate. They suggest that assumption about the linearity of I-V relationships for excitatory currents should be made with care in studies of epileptiform events. This is the first study of AMPAR, GABAAR, and NMDAR-mediated synaptic conductance dynamics in cortical pyramidal neurons during interictal discharge (IID)
Summary
A great many in vitro and in vivo studies have focused on revealing the mechanisms underlying seizures and epilepsy and their treatments, but seizures in many patients with mesial temporal lobe epilepsy remain poorly controlled by antiepileptic drugs (Téllez-Zenteno and HernándezRonquillo, 2012). To understand the mechanisms of seizure generation and termination, it is important to know the dynamics of the balance between excitation and inhibition and the changes in synaptic conductance during various stages of epileptiform discharge These mechanisms are easier to investigate in in vitro studies. We estimated AMPAR-, GABAAR-, and NMDAR-mediated synaptic conductances during two distinct types of interictal discharges (IIDs) in rat cortical pyramidal neurons of the combined hippocampus–entorhinal cortex slices using dual whole-cell current- and/or voltageclamp recordings. These conductances were larger than corresponding excitatory and inhibitory conductances calculated based on an assumption about the linearity of IV relationships for currents. The obtained curves for AMPAR-, GABAAR- and NMDAR-mediated synaptic conductances during IIDs may aid further experimental and modeling studies
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