RNA Polymerase 1 Is Transiently Regulated by Seizures and Plays a Role in a Pharmacological Kindling Model of Epilepsy

Aruna Vashishta, Lukasz P. Slomnicki, Maciej Pietrzak, Scott C Smith, Murali Kolikonda, Shivani P. Naik, Rosanna Parlato, Michal Hetman

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Ribosome biogenesis, including the RNA polymerase 1 (Pol1)-mediated transcription of rRNA, is regulated by the pro-epileptogenic mTOR pathway. Therefore, hippocampal Pol1 activity was examined in mouse models of epilepsy including kainic acid- and pilocarpine-induced status epilepticus (SE) as well as a single seizure in response to pentylenetetrazole (PTZ). Elevated 47S pre-rRNA levels were present acutely after induction of SE suggesting activation of Pol1. Conversely, after a single seizure, 47S pre-rRNA was transiently downregulated with increased levels of unprocessed 18S rRNA precursors in the cornu Ammonis (CA) region. At least in the dentate gyrus (DG), the pilocarpine SE-mediated transient activation of Pol1 did not translate into long-term changes of pre-rRNA levels or total ribosome content. Unaltered hippocampal ribosome content was also found after a 20-day PTZ kindling paradigm with increasing pro-convulsive effects of low dose PTZ that was injected every other day. However, after selectively deleting the essential Pol1 co-activator, transcription initiation factor-1A (Tif1a/Rrn3) from excitatory neurons, PTZ kindling was impaired while DG total ribosome content was moderately reduced and no major neurodegeneration was observed throughout the hippocampus. Therefore, Pol1 activity of excitatory neurons is required for PTZ kindling. As seizures affect ribosome biogenesis without long-term effects on the total ribosome content, such a requirement may be associated with a need to produce specialized ribosomes that promote pro-epileptic plasticity.

Original languageEnglish (US)
Pages (from-to)8374-8387
Number of pages14
JournalMolecular Neurobiology
Volume55
Issue number11
DOIs
StatePublished - Nov 1 2018
Externally publishedYes

Fingerprint

DNA-Directed RNA Polymerases
Ribosomes
Pentylenetetrazole
Epilepsy
Seizures
Pharmacology
RNA Precursors
Status Epilepticus
Pilocarpine
Dentate Gyrus
Hippocampus
Neurons
Peptide Initiation Factors
Kainic Acid
Transcription Factors
Down-Regulation

Keywords

  • Epileptogenesis
  • Hippocampus
  • Kindling
  • Mouse
  • Nucleolus
  • Pentylenetetrazole
  • Pilocarpine
  • Ribosomal biogenesis
  • Ribosome
  • RNA polymerase 1
  • Status epilepticus
  • Temporal lobe epilepsy

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

RNA Polymerase 1 Is Transiently Regulated by Seizures and Plays a Role in a Pharmacological Kindling Model of Epilepsy. / Vashishta, Aruna; Slomnicki, Lukasz P.; Pietrzak, Maciej; Smith, Scott C; Kolikonda, Murali; Naik, Shivani P.; Parlato, Rosanna; Hetman, Michal.

In: Molecular Neurobiology, Vol. 55, No. 11, 01.11.2018, p. 8374-8387.

Research output: Contribution to journalArticle

Vashishta, A, Slomnicki, LP, Pietrzak, M, Smith, SC, Kolikonda, M, Naik, SP, Parlato, R & Hetman, M 2018, 'RNA Polymerase 1 Is Transiently Regulated by Seizures and Plays a Role in a Pharmacological Kindling Model of Epilepsy', Molecular Neurobiology, vol. 55, no. 11, pp. 8374-8387. https://doi.org/10.1007/s12035-018-0989-9
Vashishta, Aruna ; Slomnicki, Lukasz P. ; Pietrzak, Maciej ; Smith, Scott C ; Kolikonda, Murali ; Naik, Shivani P. ; Parlato, Rosanna ; Hetman, Michal. / RNA Polymerase 1 Is Transiently Regulated by Seizures and Plays a Role in a Pharmacological Kindling Model of Epilepsy. In: Molecular Neurobiology. 2018 ; Vol. 55, No. 11. pp. 8374-8387.
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