title: Hyperactive somatostatin interneurons contribute to excitotoxicity in neurodegenerative disorders.
abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative disorders whose pathogenesis remains largely unknown. Using TDP-43(A315T) mice, an ALS and FTD model with marked cortical pathology, we found that hyperactive somatostatin interneurons disinhibited layer 5 pyramidal neurons (L5-PNs) and contributed to their excitotoxicity. Focal ablation of somatostatin interneurons efficiently restored normal excitability of L5-PNs and alleviated neurodegeneration, suggesting a new therapeutic target for ALS and FTD.
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, USA.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Liang
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: David
authors.initials: D
authors.lastname: Schroeder
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Zhong-Wei
authors.initials: ZW
authors.lastname: Zhang
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 333 Cassell Drive, Baltimore, MD 21224, USA.|The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Da-Ting
authors.initials: DT
authors.lastname: Lin
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D007395:Interneurons / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009924:Organ Culture Techniques; D017966:Pyramidal Cells / Q000378:metabolism; D013004:Somatostatin / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human; D013004:Somatostatin