Hyperactive somatostatin interneurons contribute to excitotoxicity in neurodegenerative disorders

Nat Neurosci. 2016 Apr;19(4):557-559. doi: 10.1038/nn.4257. Epub 2016 Feb 22.

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