Altered glutamatergic tone reveals two distinct resting state networks at the cellular level in hippocampal sclerosis

Jyotirmoy Banerjee,Aparna Banerjeedixit,Bhargavi Ramanujam,Arpna Srivastava,Chitra Sarkar,P Sarat Chandra,Aanchal Kakkar,Manjari Tripathi

doi:10.1038/s41598-017-00358-7

Jyotirmoy Banerjee, Aparna Banerjeedixit + Show 6 more

Open Access

https://doi.org/10.1038/s41598-017-00358-7

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Abstract

Hippocampal sclerosis (HS), the most common subset of drug-resistant epilepsy (DRE), is associated with large-scale network abnormalities, even under resting state. We studied the excitatory postsynaptic currents (EPSCs) recorded from pyramidal neurons in resected samples under resting conditions from the hippocampal and anterior temporal lobe (ATL) obtained from patients with HS (n = 14) undergoing resective surgery. We observed higher frequency and amplitude of spontaneous EPSCs in both the samples compared to non-seizure control samples. Application of tetrodotoxin (TTX) reduced the frequency of spontaneous EPSCs by 49.6 ± 4.3% and 61.8 ± 6.2% in the hippocampal and ATL samples, respectively. The magnitude of reduction caused by TTX with respect to non-seizure controls was significantly higher in the ATL samples than in the hippocampal samples. The magnitude of the change in the expression of the NR2A subunit of the NMDA receptors also varied in these two regions. Thus, the mechanism of hyperexcitabilty mediated by glutamatergic network reorganization in the hippocampal region is different from that in the ATL region of patients with HS, suggesting two independent resting-state networks at the cellular level. Taken together, these findings will improve the understanding of the broadly distributed resting-state networks in HS.

Highlights

The most common form of drug-resistant epilepsy (DRE) is hippocampal sclerosis (HS), where the mesial temporal lobe structures are involved in seizure generation through abnormal neuronal networks[1]
The present results disclose evidence that supports the concepts that i) two resting-state networks are present in patients with Hippocampal sclerosis (HS), one arising from the hippocampus and the other from the anterior temporal lobe; and ii) the spontaneous glutamatergic tone varies in resected brain specimens obtained from these regions, potentially mediated by two independent cellular mechanisms
The frequency of the glutamatergic excitatory postsynaptic currents (EPSCs) recorded from pyramidal neurons in the hippocampal samples of HS patients were higher compared to the non-seizure controls[12]

Summary

Introduction

The most common form of drug-resistant epilepsy (DRE) is hippocampal sclerosis (HS), where the mesial temporal lobe structures (including the hippocampus, amygdala and other enterorhinal structures) are involved in seizure generation through abnormal neuronal networks[1]. Functional MRI (fMRI) studies have suggested that in temporal lobe epilepsy, even the spontaneous activity of networks is affected[10] More recently it has been shown in patients with HS that alteration in electrophysiologic functional hubs leads to pathophysiologic brain network reorganization, even under resting-state[11]. We showed that under resting conditions, spontaneous EPSCs on pyramidal neurons were higher in resected hippocampal samples obtained from patients with HS12, suggesting a glutamatergic network reorganization in the hippocampus. It is not known if the extent of change in excitatory synaptic transmission is similar in the extra-hippocampal regions of patients with HS. To further examine at the molecular level alterations that may lead to the generation of abnormal networks, we analyzed the mRNA levels of the NR2A and NR2B subunits using quantitative PCR and quantified the protein levels of NR2A and NR2B using western blotting analyses in both regions

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