Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly
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, mi...
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doaj-f69832bdd4e64832a864dd70d135a5922021-05-05T21:41:14ZengeLife Sciences Publications LtdeLife2050-084X2020-11-01910.7554/eLife.62373Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephalyTyler G Ekins0https://orcid.org/0000-0002-9801-4843Vivek Mahadevan1https://orcid.org/0000-0002-0805-827XYajun Zhang2James A D'Amour3https://orcid.org/0000-0002-8144-3692Gülcan Akgül4Timothy J Petros5Chris J McBain6https://orcid.org/0000-0002-5909-0157Program in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States; NIH-Brown University Graduate Partnership Program, Providence, United StatesProgram in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United StatesProgram in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United StatesProgram in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States; Postdoctoral Research Associate Training Program, National Institute of General Medical Sciences, Bethesda, United StatesProgram in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United StatesProgram in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United StatesProgram in Developmental Neurobiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United StatesType 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.https://elifesciences.org/articles/62373lissencephalyhippocampusparvalbuminfast-spikingmigrationepilepsy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tyler G Ekins Vivek Mahadevan Yajun Zhang James A D'Amour Gülcan Akgül Timothy J Petros Chris J McBain |
spellingShingle |
Tyler G Ekins Vivek Mahadevan Yajun Zhang James A D'Amour Gülcan Akgül Timothy J Petros Chris J McBain Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly eLife lissencephaly hippocampus parvalbumin fast-spiking migration epilepsy |
author_facet |
Tyler G Ekins Vivek Mahadevan Yajun Zhang James A D'Amour Gülcan Akgül Timothy J Petros Chris J McBain |
author_sort |
Tyler G Ekins |
title |
Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly |
title_short |
Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly |
title_full |
Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly |
title_fullStr |
Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly |
title_full_unstemmed |
Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly |
title_sort |
emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type i lissencephaly |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2020-11-01 |
description |
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. |
topic |
lissencephaly hippocampus parvalbumin fast-spiking migration epilepsy |
url |
https://elifesciences.org/articles/62373 |
work_keys_str_mv |
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