Mice with conditional NeuroD1 knockout display reduced aberrant hippocampal neurogenesis but no change in epileptic seizures

Exp Neurol. 2017 Jul;293:190-198. doi: 10.1016/j.expneurol.2017.04.005. Epub 2017 Apr 18.

Abstract

Adult neurogenesis is significantly increased in the hippocampus of rodent models of temporal lobe epilepsy (TLE). These adult-generated neurons have recently been shown to play a contributing role in the development of spontaneous recurrent seizures (SRS). In order to eventually target pro-epileptic adult neurogenesis in the clinical setting, it will be important to identify molecular players involved in the control of aberrant neurogenesis after seizures. Here, we focused on NeuroD1 (ND1), a member of the bHLH family of transcription factors previously shown to play an essential role in the differentiation and maturation of adult-generated neurons in the hippocampus. Wild-type mice treated with pilocarpine to induce status epilepticus (SE) showed a significant up-regulation of NeuroD1+ immature neuroblasts located in both the granule cell layer (GCL), and ectopically localized to the hilar region of the hippocampus. As expected, conditional knockout (cKO) of NeuroD1 in Nestin-expressing stem/progenitors and their progeny led to a reduction in the number of NeuroD1+ adult-generated neurons after pilocarpine treatment compared to WT littermates. Surprisingly, there was no change in SRS in NeuroD1 cKO mice, suggesting that NeuroD1 cKO fails to reduce aberrant neurogenesis below the threshold needed to impact SRS. Consistent with this conclusion, the total number of adult-generated neurons in the pilocarpine model, especially the total number of Prox1+ hilar ectopic granule cells were unchanged after NeuroD1 cKO, suggesting strategies to reduce SRS will need to achieve a greater removal of aberrant adult-generated neurons.

Keywords: NeuroD1; Neurogenesis; Pilocarpine; Seizure; Temporal lobe epilepsy; Therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / deficiency*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Disease Models, Animal
  • Epilepsy / chemically induced
  • Epilepsy / genetics*
  • Epilepsy / pathology*
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Hippocampus / physiopathology*
  • Homeodomain Proteins / metabolism
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism
  • Muscarinic Agonists / toxicity
  • N-Methylscopolamine / toxicity
  • Nestin / genetics
  • Nestin / metabolism
  • Neurogenesis / drug effects
  • Neurogenesis / genetics
  • Neurogenesis / physiology*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuropeptides / metabolism
  • Pilocarpine / toxicity
  • Tumor Suppressor Proteins / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / genetics*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • Luminescent Proteins
  • Microtubule-Associated Proteins
  • Muscarinic Agonists
  • Nestin
  • Neurod1 protein, mouse
  • Neuropeptides
  • Tumor Suppressor Proteins
  • doublecortin protein
  • prospero-related homeobox 1 protein
  • Pilocarpine
  • N-Methylscopolamine