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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, N.I.H., Intramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
DNA-Binding Proteins / biosynthesis
-
DNA-Binding Proteins / genetics
-
Humans
-
Inhibitory Postsynaptic Potentials / physiology
-
Interneurons / metabolism*
-
Interneurons / pathology*
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Transgenic
-
Neurodegenerative Diseases / genetics
-
Neurodegenerative Diseases / metabolism*
-
Neurodegenerative Diseases / pathology*
-
Organ Culture Techniques
-
Pyramidal Cells / metabolism
-
Somatostatin / genetics
-
Somatostatin / metabolism*
Substances
-
DNA-Binding Proteins
-
TARDBP protein, human
-
Somatostatin