Seizure-Induced Potentiation of AMPA Receptor-Mediated Synaptic Transmission in the Entorhinal Cortex

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).

Short-term Epileptiform Activity Potentiates Excitatory Synapses but does not Affect Intrinsic Membrane Properties of Pyramidal Neurons in the Rat Hippocampus <em>in Vitro</em>

“…Change in AMPAR-mediated transmission can be triggered by a 10-20-min period of epileptiform activity, as demonstrated in the in vitro epilepsy model [62] and pilocarpine model [61]. Peak AMPAR-mediated responses have been increased 2-fold during 4-AP-induced epileptiform activity in the entorhinal cortex, remained potentiated 15 min after short-term epileptiform activity in vitro, and this potentiation was shown to be NMDAR-dependent and at least partly mediated by incorporation of calcium-permeable AMPARs [21]. There are multiple reports of changes in AMPAR protein expression levels and AMPAR subunit phosphorylation in the hippocampus several hours after seizures.…”

“…Although most mesial temporal lobe structures are highly susceptible to seizures, the hippocampal area demonstrates the heaviest damage in response to seizure activity [13,14]. Several mechanisms can provoke changes in the excitability of neuronal networks, including changes in intrinsic neuronal excitability [15][16][17], potentiation of excitatory synaptic contacts [9,[18][19][20][21], changes in synaptic inhibition [22][23][24][25], cell loss and sprouting of axons [26][27][28]. However, relatively little is known about the precise mechanisms of the network excitability increase resulting from a brief episode of epileptic activity -what specific changes occur at presynaptic and postsynaptic levels, and how these changes affect hippocampal circuit functioning.…”

Neural stem cell–specific ITPA deficiency causes neural depolarization and epilepsy

“…The amplitude of mEPSC in Itpa-cKO cells was also significantly higher than in control cells, although no significant difference was noted in the amplitude of mIPSC between Itpa-cKO cells and control cells ( Figure 6C, right, and Figure 6D, right). Seizure-like events were recently reported to induce the potentiation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor in pyramidal cells of rat entorhinal cortex (37). The increase in the amplitude of mEPSC in the entorhinal pyramidal cells of Itpa-cKO mice may also depend on the increase in presynaptic excitation observed as the frequency of mEPSC increases.…”

Modulation of AMPA Receptors by Nitric Oxide in Nerve Cells

“…The number of these receptors increases in pilocarpine-induced status epilepticus [53,54], stroke and ischemia [55,56], cognitive impairment in diabetes [57], depression [58], and amyotrophic lateral sclerosis [59]. The involvement of calcium-impermeable (CI)-and calcium-permeable (CP)-AMPARs in synaptic plasticity differs functionally and temporally.…”