Increased susceptibility to kainic acid–induced seizures in Engrailed-2 knockout mice
Abstract
The En2 gene, coding for the homeobox-containing transcription factor Engrailed-2 (EN2), has been associated to autism spectrum disorder (ASD). Due to neuroanatomical and behavioral abnormalities, which partly resemble those observed in ASD patients, En2 knockout (En2(-/-)) mice have been proposed as a model for ASD. In the mouse embryo, En2 is involved in the specification of midbrain/hindbrain regions, being predominantly expressed in the developing cerebellum and ventral midbrain, and its expression is maintained in these structures until adulthood. Here we show that in the adult mouse brain, En2 mRNA is expressed also in the hippocampus and cerebral cortex. Hippocampal En2 mRNA content decreased after seizures induced by kainic acid (KA). This suggests that En2 might also influence the functioning of forebrain areas during adulthood and in response to seizures. Indeed, a reduced expression of parvalbumin and somatostatin was detected in the hippocampus of En2(-/-) mice as compared to wild-type (WT) mice, indicating an altered GABAergic innervation of limbic circuits in En2(-/-) mice. In keeping with these results, En2(-/-) mice displayed an increased susceptibility to KA-induced seizures. KA (20 mg/kg) determined more severe and prolonged generalized seizures in En2(-/-) mice, when compared to WT animals. Seizures were accompanied by a widespread c-fos and c-jun mRNA induction in the brain of En2(-/-) but not WT mice. Long-term histopathological changes (CA1 cell loss, upregulation of neuropeptide Y) also occurred in the hippocampus of KA-treated En2(-/-) but not WT mice. These findings suggest that En2(-/-) mice might be used as a novel tool to study the link between epilepsy and ASD.
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Canonical ASD mouse models were shown to display a reduction in the number of PV-immunoreactive cells in various brain regions.
“As already reported in several studies [47, 72–74] canonical ASD mouse models were shown to display a reduction in the number of PV-immunoreactive cells in various brain regions.”
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- Authors
- Tripathi, P. P., Sgadò, P., Scali, M., Viaggi, C., Casarosa, S., Simon, H. H., Vaglini, F., Corsini, G. U., & Bozzi, Y.
- Affiliations
- Scuola Normale Superiore (IT)
- University of Pisa (IT)
- Heidelberg University (DE)
- Neuroscience Institute (IT)
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 159
- Issue
- 2
- Pages
- 842-849
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W2035900692
- Cited by
- 74
- References
- 48
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 5 · 2020: 5 · 2019: 4 · 2018: 6 · 2017: 4 · 2016: 7 · 2015: 5 · 2014: 11 · 2013: 4 · 2012: 3
- FWCI
- 2.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Trento) (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- Engrailed-2, autism spectrum disorder, kainic acid-induced seizures, epilepsy, hippocampus, GABAergic interneurons, parvalbumin, somatostatin, c-fos, c-Jun, neuropeptide Y, homeodomain transcription factor, limbic circuits
- MeSH terms
- Engrailed 2 Protein, Animals, Brain, Disease Susceptibility, Gene Expression Regulation, Kainic Acid, Mice, Inbred C57BL, Nerve Tissue Proteins, Parvalbumins, Reaction Time, RNA, Messenger, Seizures, Somatostatin, Time Factors, Proto-Oncogene Proteins c-jun, Proto-Oncogene Proteins c-fos, Mice, Knockout, Homeodomain Proteins, Excitatory Amino Acid Agonists, Mice
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