Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly

Elife. 2020 Nov 5;9:e62373. doi: 10.7554/eLife.62373.

Abstract

Type I lissencephaly is a neuronal migration disorder caused by haploinsuffiency of the PAFAH1B1 (mouse: Pafah1b1) gene and is characterized by brain malformation, developmental delays, and epilepsy. Here, we investigate the impact of Pafah1b1 mutation on the cellular migration, morphophysiology, microcircuitry, and transcriptomics of mouse hippocampal CA1 parvalbumin-containing inhibitory interneurons (PV+INTs). We find that WT PV+INTs consist of two physiological subtypes (80% fast-spiking (FS), 20% non-fast-spiking (NFS)) and four morphological subtypes. We find that cell-autonomous mutations within interneurons disrupts morphophysiological development of PV+INTs and results in the emergence of a non-canonical 'intermediate spiking (IS)' subset of PV+INTs. We also find that now dominant IS/NFS cells are prone to entering depolarization block, causing them to temporarily lose the ability to initiate action potentials and control network excitation, potentially promoting seizures. Finally, single-cell nuclear RNAsequencing of PV+INTs revealed several misregulated genes related to morphogenesis, cellular excitability, and synapse formation.

Keywords: epilepsy; fast-spiking; hippocampus; lissencephaly; migration; mouse; neuroscience; parvalbumin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism*
  • Animals
  • Classical Lissencephalies and Subcortical Band Heterotopias / pathology*
  • Electrophysiological Phenomena
  • Gene Expression Regulation / physiology
  • Hippocampus / cytology*
  • Interneurons / metabolism*
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Parvalbumins / metabolism*

Substances

  • Microtubule-Associated Proteins
  • Parvalbumins
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • Pafah1b1 protein, mouse