---
title: "Parvalbumin interneuron dysfunction and dentate gyrus dysregulation drive epileptogenesis in Angel"
id: "biorxiv-5-parvalbumin-interneurons-and-dentate-gyrus-homeostatic-dysregulation-shape"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-5-parvalbumin-interneurons-and-dentate-gyrus-homeostatic-dysregulation-shape"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.17.752419v1?rss=1"
published_at: "2026-09-19T10:43:17.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Parvalbumin interneuron dysfunction and dentate gyrus dysregulation drive epileptogenesis in Angel
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-5-parvalbumin-interneurons-and-dentate-gyrus-homeostatic-dysregulation-shape
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.17.752419v1?rss=1)
- **Published At:** 2026-09-19T10:43:17.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study uses an Angelman syndrome (AS) mouse model lacking the maternal **Ube3a** allele to investigate mechanisms that convert seizure resistance into seizure susceptibility during kindling. - AS model mice show heightened susceptibility to seizure kindling compared with controls, providing a platform to study epileptogenesis. - Selective deletion of maternal Ube3a in **parvalbumin (PV+) interneurons** reproduces (phenocopies) the enhanced epileptogenesis seen in full AS model mice, identifying PV+ interneurons as critical inhibitory gatekeepers. - Broad restoration of **UBE3A** expression in GABAergic neurons reverses the seizure-prone phenotype and confers seizure resistance, implicating inhibitory neuron UBE3A as protective. - Pathological remodeling of the **extracellular matrix (ECM)** in the **dentate gyrus** correlates with post-kindling seizure susceptibility, highlighting the dentate gyrus as a region of particular relevance. - Electrophysiologic analyses reveal a two-hit phenomenon: kindling fails to recruit compensatory inhibition onto dentate granule cells and instead promotes maladaptive intrinsic hyperexcitability of those cells. - The combined findings link cell type–specific inhibitory dysfunction and impaired homeostatic plasticity to epileptogenesis in AS model mice, supporting circuit-based therapeutic strategies. - The authors report no competing interests and acknowledge funding from the Simons Foundation (SFARI) and multiple NINDS and NICHD awards as listed in the source.
## Clinical Analysis & Structured Key Points
Parvalbumin interneurons and dentate gyrus homeostatic dysregulation shape epileptogenesis in Angelman syndrome model mice | bioRxiv Skip to main content New Results Parvalbumin interneurons and dentate gyrus homeostatic dysregulation shape epileptogenesis in Angelman syndrome model mice View ORCID Profile Nicholas W Ringelberg , View ORCID Profile David W Kipp , Renée E Mayfield , View ORCID Profile Lucas M James , View ORCID Profile Audrey L Smith , View ORCID Profile Paul B Manis , View ORCID Profile Alain C Burette , View ORCID Profile Michael R Kasten , View ORCID Profile Benjamin D Philpot doi: https://doi.org/10.64898/2026.09.17.752419 Nicholas W Ringelberg 1 University of North Carolina School of Medicine; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nicholas W Ringelberg David W Kipp 2 University of North Carolina at Chapel Hill; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for David W Kipp Renée E Mayfield 2 University of North Carolina at Chapel Hill; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Lucas M James 3 UNC School of Medicine Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Lucas M James Audrey L Smith 3 UNC School of Medicine Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Audrey L Smith Paul B Manis 3 UNC School of Medicine Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Paul B Manis Alain C Burette 3 UNC School of Medicine Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Alain C Burette Michael R Kasten 3 UNC School of Medicine Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Michael R Kasten Benjamin D Philpot 3 UNC School of Medicine Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Benjamin D Philpot For correspondence: bphilpot{at}med.unc.edu Abstract Info/History Metrics Supplementary material Preview PDF Abstract Understanding how neural circuits transition from seizure-resistant to seizure-prone is essential for developing improved epilepsy therapies. Here, we study this process by leveraging the heightened susceptibility to seizure kindling of Angelman syndrome (AS) model mice, which lack the maternal Ube3a (mUbe3a) allele. We identify parvalbumin-expressing (PV+) interneurons as critical gatekeepers; selective mUbe3a deletion in PV+ neurons phenocopies enhanced AS epileptogenesis, whereas restoring UBE3A broadly in GABAergic neurons confers seizure resistance. Further, pathological remodeling of the extracellular matrix in the dentate gyrus faithfully tracks with post-kindling seizure susceptibility, highlighting this region's particular relevance to enhanced epileptogenesis. Mechanistically, we uncover a 'two-hit' electrophysiologic phenomenon in AS model mice: kindling fails to recruit compensatory inhibition onto dentate granule cells and instead drives their maladaptive intrinsic hyperexcitability. Together, these findings link cell type-specific inhibitory dysfunction and altered homeostatic plasticity to epileptogenesis, suggesting future circuit-based treatment strategies. Competing Interest Statement The authors have declared no competing interest. Funder Information Declared Simons Foundation , SFARI 702556 National Institute of Neurological Disorders and Stroke, https://ror.org/01s5ya894 , R01NS129914 , R01NS131615 , R01NS145518 Eunice Kennedy Shriver National Institute of Child Health and Human Development, https://ror.org/04byxyr05 , F30HD111296 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Back to top Previous Next Posted September 19, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Parvalbumin interneurons and dentate gyrus homeostatic dysregulation shape epileptogenesis in Angelman syndrome model mice Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Parvalbumin interneurons and dentate gyrus homeostatic dysregulation shape epileptogenesis in Angelman syndrome model mice Nicholas W Ringelberg , David W Kipp , Renée E Mayfield , Lucas M James , Audrey L Smith , Paul B Manis , Alain C Burette , Michael R Kasten , Benjamin D Philpot bioRxiv 2026.09.17.752419; doi: https://doi.org/10.64898/2026.09.17.752419 Share This Article: Copy Citation Tools Parvalbumin interneurons and dentate gyrus homeostatic dysregulation shape epileptogenesis in Angelman syndrome model mice Nicholas W Ringelberg , David W Kipp , Renée E Mayfield , Lucas M James , Audrey L Smith , Paul B Manis , Alain C Burette , Michael R Kasten , Benjamin D Philpot bioRxiv 2026.09.17.752419; doi: https://doi.org/10.64898/2026.09.17.752419 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (8011) Biochemistry (18737) Bioengineering (14888) Bioinformatics (44414) Biophysics (22594) Cancer Biology (19721) Cell Biology (26898) Clinical Trials (138) Developmental Biology (13964) Ecology (21005) Epidemiology (2067) Evolutionary Biology (25454) Genetics (16164) Genomics (23503) Immunology (18702) Microbiology (42482) Molecular Biology (18058) Neuroscience (93429) Paleontology (700) Pathology (2977) Pharmacology and Toxicology (5094) Physiology (8114) Plant Biology (15999) Scientific Communication and Education (2095) Synthetic Biology (4560) Systems Biology (10235) Zoology (2391)
## Related Clinical Research

- [Outcome Measure Feasibility and Validity in STXBP1-Related Disorders: Bayley-4, PDMS-3, GMFM-66 Fi](https://medichelpline.com/clinical-feed/medrxiv-7-feasibility-and-validity-of-clinical-outcome-measures-in-a-prospective-natural.md)
- [Neurological involvement in localized scleroderma: clinical features and neuroimaging patterns](https://medichelpline.com/clinical-feed/frontiers-in-immunology-9-neurological-involvement-in-localized-scleroderma-a-systematic-review-of.md)
- [Functional electrical stimulation for major depressive disorder: Pilot randomized sham-controlled](https://medichelpline.com/clinical-feed/plos-one-22-functional-electrical-stimulation-for-major-depressive-disorder-protocol-for-a.md)
- [Adherence to anti-seizure medications in Buikwe and Mukono, Uganda: prevalence, associated factors](https://medichelpline.com/clinical-feed/plos-one-9-adherence-to-anti-seizure-medications-among-persons-living-with-epilepsy.md)
- [Large language model to automate risk-of-bias (QUIPS) assessments in neurology prognosis reviews](https://medichelpline.com/clinical-feed/medrxiv-5-a-large-language-model-for-risk-of-bias-assessment-in-systematic-reviews-of.md)

## Navigation
- [← Back to Neurology Feed](https://medichelpline.com/clinical-feed/neurology.md)
- [← All Clinical Specialties](https://medichelpline.com/clinical-feed.md)
## Medical & Regulatory Disclaimer

> [!CAUTION]
> MedicHelpline content is structured for research, educational, and professional discovery purposes. It does not constitute individual medical advice, clinical diagnosis, or treatment recommendations.
> Always verify dosing, contraindications, and regulatory alerts against official product labeling and primary regulatory sources before clinical decision-making.