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Role of Altered Expression, Activity and Sub-cellular Distribution of Various Histone Deacetylases (HDACs) in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis

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Abstract

Histone deacetylases (HDACs) have been described to have both neurotoxic and neuroprotective roles, and partly, depend on its sub-cellular distribution. HDAC inhibitors have a long history of use in the treatment of various neurological disorders including epilepsy. Key role of HDACs in GABAergic neurotransmission, synaptogenesis, synaptic plasticity and memory formation was demonstrated whereas very less is known about their role in drug-resistant epilepsy pathologies. The present study was aimed to investigate the changes in the expression of HDACs, activity and its sub-cellular distribution in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) patients. For this study, surgically resected hippocampal tissue specimens of 28 MTLE-HS patients and 20 hippocampus from post-mortem cases were obtained. Real-time PCR was done to analyse the mRNA expression. HDAC activity and the protein levels of HDACs in cytoplasm as well as nucleus were measured spectrophotometrically. Further, sub-cellular localization of HDACs was characterized by immunofluorescence. Significant upregulation of HDAC1, HDAC2, HDAC4, HDAC5, HDAC6, HDAC10 and HDAC11 mRNA were observed in MTLE-HS. Alterations in the mRNA expression of glutamate and gamma-aminobutyric acid (GABA) receptor subunits have been also demonstrated. We observed significant increase of HDAC activity and nuclear level of HDAC1, HDAC2, HDAC5 and HDAC11 in the hippocampal samples obtained from patients with MTLE-HS. Moreover, we found altered cytoplasmic level of HDAC4, HDAC6 and HDAC10 in the hippocampal sample obtained from patients with MTLE-HS. Alterations in the level of HDACs could potentially be part of a dynamic transcription regulation associated with MTLE-HS. Changes in cytoplasmic level of HDAC4, 6 and 10 suggest that cytoplasmic substrates may play a crucial role in the pathophysiology of MTLE-HS. Knowledge regarding expression pattern and sub-cellular distribution of HDACs may help to devise specific HDACi therapy for epilepsy.

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Data Availability

All data generated or analysed in the current study are available from the corresponding author on reasonable request.

Abbreviations

AIIMS:

All India Institute of Medical Sciences

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

ATF4:

Activating transcription factor 4

BSA:

Bovine serum albumin

CA:

Cornu ammonis

COX-2:

Cyclooxygenase-2

DAB:

Diaminobenzidine (DAB) solution

DAPI:

4′,6-Diamidino-2-phenylindole

ELISA:

Enzyme-linked immunosorbent assay

EEG:

Electroencephalogram

FDG-PET:

Fluoro-2-deoxyglucose positron emission tomography

FITC:

Fluorescein isothiocyanate

GABA:

Gamma-aminobutyric acid

GFAP:

Glial fibrillary acidic protein

GAT:

GABA transporter

GAD65:

Glutamate decarboxylase 65

GLT-1:

Glutamate transporter 1

HDAC:

Histone deacetylase

HDACi:

Histone deacetylase inhibitor

HE:

Hematoxylin–eosin

HIF-1A:

Hypoxia-inducible factor 1 alpha

HPRT:

Hypoxanthine–guanine phosphoribosyltransferase

HS:

Hippocampal sclerosis

Hsp90:

Heat shock protein 90

IHC:

Immunohistochemistry

MEG:

Magnetoencephalography

MMP:

Matrix metalloproteinase

MRI:

Magnetic resonance imaging

MSA:

Multiple system atrophy

MTLE-HS:

Mesial temporal lobe epilepsy with hippocampal sclerosis

NAD:

Nicotinamide adenine dinucleotide

PBS:

Phosphate buffered saline

RNA:

Ribonucleic acid

SE:

Status epilepticus

STAT1:

Signal transducer and activator of transcription 1

TLE:

Temporal lobe epilepsy

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Acknowledgements

The authors are indebted to all the patients and their family for participating in this study. This work is funded by the Intramural Grant of AIIMS (A449), MEG resource facility, funded by Department of Biotechnology, Ministry of Science & Technology, Govt. of India [BT/MED/122/SP24580/2018] and MG grant from ACBR.

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Authors and Affiliations

  1. Centre of Excellence for Epilepsy, AIIMS, New Delhi, India

    Arpna Srivastava, Jyotirmoy Banerjee, Manjari Tripathi, P. Sarat Chandra & Aparna Banerjee Dixit

  2. Department of Neurosurgery, AIIMS, New Delhi, India

    Arpna Srivastava, P. Sarat Chandra & Ramesh Doddamani

  3. Department of Biophysics, AIIMS, New Delhi, India

    Jyotirmoy Banerjee & Vivek Dubey

  4. Department of Neurology, AIIMS, New Delhi, India

    Manjari Tripathi

  5. Department of Pathology, AIIMS, New Delhi, India

    M. C. Sharma

  6. Department of Forensic Medicine and Toxicology, AIIMS, New Delhi, India

    Sanjeev Lalwani

  7. National Institute of Pathology, New Delhi, India

    Fouzia Siraj

  8. Dr B R Ambedkar Centre for Biomedical Research, University of Delhi, New Delhi, India

    Aparna Banerjee Dixit

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  1. Arpna Srivastava
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Contributions

A.S. designed the research, performed research, analysed the data and wrote the paper A.B.D. designed the research, and wrote the paper. V.D. performed research. M.T. designed the research. S.L. provided the autopsy samples for research. M.C.S. and F.S analysed the histopathological features and IHC. P.S.C. and R.D. provided clinical samples, designed the research. J.B. designed the research and wrote the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ramesh Doddamani or Aparna Banerjee Dixit.

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The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

The present study was conducted in accordance with the Declaration of Helsinki and was approved by the Institute Ethics Committee, AIIMS, New Delhi (Ref. No. IEC-198/01.04.2016). Informed and written consent was obtained from all the patients, their parents, or legal guardians if patients were underage.

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All donors gave informed consent for the use of their tissue and medical files for research purposes.

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Srivastava, A., Banerjee, J., Dubey, V. et al. Role of Altered Expression, Activity and Sub-cellular Distribution of Various Histone Deacetylases (HDACs) in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis. Cell Mol Neurobiol 42, 1049–1064 (2022). https://doi.org/10.1007/s10571-020-00994-0

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