Abstract
Excessive excitation is considered one of the key mechanisms underlying epileptic seizures. We investigated changes in the evoked postsynaptic responses of medial entorhinal cortex (ERC) pyramidal neurons by seizure-like events (SLEs), using the modified 4-aminopyridine (4-AP) model of epileptiform activity. Rat brain slices were perfused with pro-epileptic solution contained 4-AP and elevated potassium and reduced magnesium concentration. We demonstrated that 15-min robust epileptiform activity in slices leads to an increase in the amplitude of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated component of the evoked response, as well as an increase in the polysynaptic γ-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptor-mediated components. The increase in AMPA-mediated postsynaptic conductance depends on NMDA receptor activation. It persists for at least 15 min after the cessation of SLEs and is partly attributed to the inclusion of calcium-permeable AMPA receptors in the postsynaptic membrane. The mathematical modeling of the evoked responses using the conductance-based refractory density (CBRD) approach indicated that such augmentation of the AMPA receptor function and depolarization by GABA receptors results in prolonged firing that explains the increase in polysynaptic components, which contribute to overall network excitability. Taken together, our data suggest that AMPA receptor enhancement could be a critical determinant of sustained status epilepticus (SE).
Highlights
Status epilepticus (SE) is a common emergency condition with a considerable mortality rate (Betjemann and Lowenstein, 2015) that can result from the activation of currently unknown mechanisms that sustain seizures (Joshi and Kapur, 2018)
To investigate seizure-like events (SLEs)-induced changes in the evoked responses, two sets of evoked postsynaptic currents (ePSCs) were recorded at different voltages in Artificial cerebrospinal fluid (ACSF) and after the application of the pro-epileptic solution and 10–15 min of consequent epileptiform activity with at least three SLEs being detected (Figure 2B)
Our results demonstrate that even several minutes of epileptiform activity lead to the transient potentiation of postsynaptic amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor (AMPAR) in entorhinal cortex (ERC) pyramidal neurons, which is accompanied by an increase in the relative impact of CP-AMPARs on the postsynaptic response
Summary
Status epilepticus (SE) is a common emergency condition with a considerable mortality rate (Betjemann and Lowenstein, 2015) that can result from the activation of currently unknown mechanisms that sustain seizures (Joshi and Kapur, 2018). It is generally accepted that the balance between excitation and inhibition shifts towards excitation during epileptic seizures, Potentiation of AMPA Transmission in Epilepsy and most studies point towards a decrease in the efficiency of γ-aminobutyric acid (GABA)a-receptor (GABAaR) mediated inhibition as a primary cause of this imbalance (mainly due to intracellular chloride accumulation; Barmashenko et al, 2011; Glykys et al, 2014; Alfonsa et al, 2015; Raimondo et al, 2015); an increasing amount of evidence indicates that the potentiation of α-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission to hippocampal neurons can develop due to seizures (Abegg et al, 2004; Debanne et al, 2006; Joshi et al, 2017) The role it plays in maintaining the SE and the long-term consequences of SE-induced changes in the brain circuitry are not fully understood. In some studies on the plastic changes of AMPAR-mediated transmission, the induced epileptiform activity in a model object or epileptic seizures in animals lasted much longer than that it could be supposed to occur in patients (Abegg et al, 2004), which can lead to much stronger plastic changes in the excitatory synapses than is possible in clinics
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