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

Abstract

Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy in humans, and is often developed after an initial precipitating brain injury. This form of epilepsy is frequently resistant to pharmacological treatment; therefore, the prevention of TLE is the prospective approach to TLE therapy. The lithium-pilocarpine model in rats replicates some of the main features of TLE in human, including the pathogenic mechanisms of cell damage and epileptogenesis after a primary brain injury. In the present study, we investigated changes in the properties of glutamatergic transmission during the first 3 days after pilocarpine-induced acute seizures in Wistar rats (PILO-rats). Using RT-PCR and electrophysiological techniques, we compared the changes in the temporal cortex (TC) and hippocampus, brain areas differentially affected by seizures. On the first day, we found a transient increase in a ratio of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl d-aspartate (NMDA) receptors in the excitatory synaptic response in pyramidal neurons of the CA1 area of the dorsal hippocampus, but not in the TC. This was accompanied by an increase in the slope of input-output (I/O) curves for fEPSPs recorded in CA1, suggesting an enhanced excitability in AMPARs in this brain area. There was no difference in the AMPA/NMDA ratio in control rats on the third day. We also revealed the alterations in NMDA receptor subunit composition in PILO-rats. The GluN2B/GluN2A mRNA expression ratio increased in the dorsal hippocampus but did not change in the ventral hippocampus or the TC. The kinetics of NMDA-mediated evoked EPSCs in hippocampal neurons was slower in PILO-rats compared with control animals. Ifenprodil, a selective antagonist of GluN2B-containing NMDARs, diminished the area and amplitude of evoked EPSCs in CA1 pyramidal cells more efficiently in PILO-rats compared with control animals. These results demonstrate that PILO-induced seizures lead to more severe alterations in excitatory synaptic transmission in the dorsal hippocampus than in the TC. Seizures affect the relative contribution of AMPA and NMDA receptor conductances in the synaptic response and increase the proportion of GluN2B-containing NMDARs in CA1 pyramidal neurons. These alterations disturb normal circuitry functions in the hippocampus, may cause neuron damage, and may be one of the important pathogenic mechanisms of TLE.

Enhanced synaptic transmission in the extended amygdala and altered excitability in an extended amygdala to brainstem circuit in a Dravet syndrome mouse model

“…This allowed us to calculate AMPA/NMDA ratio for each cell. Changes in AMPA/NMDA ratio are a potential hallmark for evidence of plasticity and are seen after learning and memory tasks, but also in pathologic situations such as temporal lobe epilepsy models (Amakhin et al, 2017). We found a significant increase in this ratio in DS mice in dBNST neurons (WT: 1.9±0.3 n=7 cells from 5 mice, DS: 3.3±0.4 n=14 cells from 8 mice, p=0.04, Figure 2c).…”

Astrocytic Atrophy Following Status Epilepticus Parallels Reduced Ca2+ Activity and Impaired Synaptic Plasticity in the Rat Hippocampus

“…For example, it might be affected because of the perturbations in the glutamate-glutamine cycle, such as increased extracellular levels of glutamate, loss of astrocytic glutamine synthetase, and changes in glutaminase and glutamate dehydrogenase, which are frequently encountered in patients with epilepsy (Coulter and Eid, 2012 ; Eid et al, 2016 ). Another possible reason is the changes in the production of individual subunits of NMDA receptors, which have been shown in several experimental models of epilepsy including the lithium-pilocarpine model (Di Maio et al, 2013 ; Müller et al, 2013 ; Peng et al, 2016 ; Amakhin et al, 2017 ). Hippocampal astrocytes in brain slices retain the ability to control LTP within or near their individual territories involving Ca 2+ -dependent D -serine release (Henneberger et al, 2010 ).…”

Administration of Bacterial Lipopolysaccharide during Early Postnatal Ontogenesis Induces Transient Impairment of Long-Term Synaptic Plasticity Associated with Behavioral Abnormalities in Young Rats

“…Because the amplitude of fEPSP depends mostly on the activation of AMPAR-mediated conductance [47,48], potential changes in the impact of NMDAR might be undervalued. Therefore, we investigated the relative contribution of AMPAR-and NMDAR-mediated excitatory synaptic currents.…”