Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of Type I lissencephaly
- Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States
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.
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Data generated are included in the manuscript, supporting files, and source data.
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Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development (Intramural Resarch Award)
- Chris J McBain
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mouse experiments were conducted in accordance with animal protocols approved by the National Institutes of Health (ASP# 17-045).
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of Type I lissencephaly
eLife 9:e62373.
https://doi.org/10.7554/eLife.62373
