Developmental changes in Notch1 and NLE1 expression in a genetic model of absence epilepsy

Brain Struct Funct. 2017 Aug;222(6):2773-2785. doi: 10.1007/s00429-017-1371-9. Epub 2017 Feb 16.

Abstract

Childhood absence epilepsy (CAE) is an epilepsy syndrome with seizures occurring in the early childhood, highlighting that seizures susceptibility in CAE is dependent on brain development. The Notch 1 signalling pathway is important in brain development, yet the role of the Notch1 signalling pathway in CAE remains elusive. We here explored Notch1 and its modulator notchless homologue 1 (NLE1) expression in WAG/Rij and control rats using immunohistochemistry. Functional Notch 1 effects were assessed in WAG/Rij rats in vivo. WAG/Rij rats lack the developmental increase in cortical Notch1 and NLE 1 mRNA expression seen in controls, and Notch 1 and NLE1 mRNA and protein expression were lower in somatosensory cortices of WAG/Rij rats when compared to controls. This coincided with an overall decreased cortical GFAP expression in the early development in WAG/Rij rats. These effects were region-specific as they were not observed in thalamic tissues. Neuron-to-glia ratio as a marker of the impact of Notch signalling on differentiation was higher in layer 4 of somatosensory cortex of WAG/Rij rats. Acute application of Notch 1 agonist Jagged 1 suppressed, whereas DAPT, a Notch antagonist, facilitated spike and wave discharges (SWDs) in WAG/Rij rats. These findings point to Notch1 as an important signalling pathway in CAE which likely shapes architectural organization of the somatosensory cortex, a region critically involved in developmental epileptogenesis in CAE. More immediate effects of Notch 1 signalling are seen on in vivo SWDs in CAE, pointing to the Notch 1 pathway as a possible treatment target in CAE.

Keywords: Absence epilepsy; Brain development; Electroencephalogram; Neurobiology.

MeSH terms

  • Age Factors
  • Animals
  • Antigens, Nuclear / metabolism
  • Brain Waves
  • Disease Models, Animal
  • Electrocorticography
  • Epilepsy, Absence / genetics*
  • Epilepsy, Absence / metabolism
  • Epilepsy, Absence / physiopathology
  • Gene Expression Regulation, Developmental
  • Genetic Predisposition to Disease
  • Glial Fibrillary Acidic Protein / metabolism
  • Immunohistochemistry
  • Jagged-1 Protein / administration & dosage
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Phenotype
  • Rats, Wistar
  • Real-Time Polymerase Chain Reaction
  • Receptor, Notch1 / drug effects
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism*
  • Somatosensory Cortex / drug effects
  • Somatosensory Cortex / growth & development
  • Somatosensory Cortex / metabolism*
  • Somatosensory Cortex / physiopathology
  • Thalamus / metabolism
  • Thalamus / physiopathology

Substances

  • Antigens, Nuclear
  • GFAP protein, rat
  • Glial Fibrillary Acidic Protein
  • Jagged-1 Protein
  • Microfilament Proteins
  • Nerve Tissue Proteins
  • Notch1 protein, rat
  • Rbfox3 protein, rat
  • Receptor, Notch1