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.
Data availability
Data generated are included in the manuscript, supporting files, and source data.
Article and author information
Author details
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.
Metrics
-
- 2,233
- views
-
- 266
- downloads
-
- 20
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Neuroscience
When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.
-
- Neuroscience
When navigating environments with changing rules, human brain circuits flexibly adapt how and where we retain information to help us achieve our immediate goals.
