Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer's [corrected] disease model

Nat Commun. 2014 Jun 13;5:4159. doi: 10.1038/ncomms5159.

Abstract

Amyloid plaques and tau tangles are common pathological hallmarks for Alzheimer's disease (AD); however, reducing Aβ production failed to relieve the symptoms of AD patients. Here we report a high GABA (γ-aminobutyric acid) content in reactive astrocytes in the dentate gyrus (DG) of a mouse model for AD (5xFAD) that results in increased tonic inhibition and memory deficit. We also confirm in human AD patient brains that dentate astrocytes have a high GABA content, suggesting that high astrocytic GABA level may be a novel biomarker and a potential diagnostic tool for AD. The excessive GABA in 5xFAD astrocytes is released through an astrocyte-specific GABA transporter GAT3/4, and significantly enhances tonic GABA inhibition in dentate granule cells. Importantly, reducing tonic inhibition in 5xFAD mice rescues the impairment of long-term potentiation (LTP) and memory deficit. Thus, reducing tonic GABA inhibition in the DG may lead to a novel therapy for AD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology
  • Alzheimer Disease / psychology*
  • Animals
  • Astrocytes / metabolism
  • Dentate Gyrus / cytology
  • Dentate Gyrus / metabolism*
  • Disease Models, Animal
  • Female
  • Humans
  • Long-Term Potentiation*
  • Male
  • Memory
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Receptors, GABA-A
  • gamma-Aminobutyric Acid