Summary: According to a new mathematical model of seizures, only the conductivity of the AMPA receptors in neurons in the temporal lobe significantly change, leading to stronger excitation and synaptic signals.
Source: Akson Russian Science Communication Association.
Russian scientists investigated the changes in the temporal lobe cortex of a rat brain during prolonged epileptic seizures. Despite the complex interaction of neural signals, biologists and physicists managed to build their mathematical model and identified the key factor leading to the seizures. This work was supported by the Russian Science Foundation and published in Frontiers in Cellular Neuroscience.
A person subject to epilepsy suffers from occasional convulsive seizures. The condition when the seizures follow each other after a short time is called epistatus and considered to be particularly dangerous. Although scientists know that this happen due to excessive excitation of neurons in the brain, the cause of such excitation remains unclear.
In the new study, the researchers examined the signaling processes in the cortex of the temporal lobe before and after the seizures. This area was chosen on purpose since the epilepsy associated with it is the most common. Scientists conducted their research on a rat brain cut placed in a special pro-epileptic solution that mimics convulsions in the patient’s brain tissue. To study the excitability of neurons, scientists analyzed the currents that occur in the brain cells stimulated by electricity, before and after a 15-minute epistatus.
“Neurons send each other signals that can be excitatory or inhibitory, depending on the type of target receptor on the cell membrane. For example, the first are those that react to glutamate and its analogues, the second are sensitive to gamma-aminobutyric acid or GABA. Yet GABA receptors of those suffering with the epilepsy also become exciting. There lies the main research difficulty: when several signals act on the neuron at once it is very difficult to assess their individual contribution,” says Anton Chizhov, doctor of physical and mathematical sciences, senior researcher at the Ioffe Institute of RAS and Leading Researcher at Sechenov Institute of Evolutionary Physiology and Biochemistry.
During their experiments, scientists examined the effect of amino acids (constituent proteins) on receptors of all major types (AMPA, NMDA and GABA). It turned out that each of these components of the signal after epileptic electrical discharges becomes stronger and longer. But what if this happened as a result of affecting only one amplified signal on the remaining paths? To find this out scientists created a mathematical model of interacting nerve cells system. According to the model, only the conductivity of the AMPA receptors in the network of neurons significantly changes, leading to stronger excitation of all neurons and stronger synaptic signals recorded on one nerve cell.
“Further studies showed that this is the mechanism of synaptic plasticity with the incorporation of new calcium-permeable AMPA receptors into the cell membranes. Under normal conditions, such a process in the brain is associated with memory and learning, but under pathological conditions it leads to an excitability increase up to tens of minutes. Therefore, the risk of a new convulsive discharge rises, which may lead to pathology fixation. Nevertheless, knowing that embedding calcium-permeable AMPA receptors leads to the consolidation of seizure activity, we can develop new antiepileptic drugs,” the scientist concludes.
Funding: Russian Science Foundation funded this study.
Source: Anton Chizhov – Akson Russian Science Communication Association
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to Jennifer E. Fairman, CMI, FAMI.
Original Research: Open access research for “Seizure-Induced Potentiation of AMPA Receptor-Mediated Synaptic Transmission in the Entorhinal Cortex” by Dmitry V. Amakhin, Elena B. Soboleva, Julia L. Ergina, Sergey L. Malkin, Anton V. Chizhov and Aleksey V. Zaitsev in Frontiers in Cellular Neuroscience. Published December 11 2018.
doi:10.3389/fncel.2018.00486
[cbtabs][cbtab title=”MLA”]Akson Russian Science Communication Association”How the Brain Decides Whether to Hold ’em or Fold ’em.” NeuroscienceNews. NeuroscienceNews, 7 January 2019.
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Abstract
Seizure-Induced Potentiation of AMPA Receptor-Mediated Synaptic Transmission in the Entorhinal Cortex
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).
