Homeostatic Disinhibition in the aging brain and alzheimer's disease

Marc Gleichmann, Vivian W. Chow, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


In this article, we propose that impaired efficiency of glutamatergic synaptic transmission and a compensatory reduction in inhibitory neurotransmission, a process called homeostatic dishinhibition, occurs in the aging brain and more dramatically in Alzheimer's disease (AD). Homeostatic disinhibition may help understand certain features of the aging brain and AD, including: 1) the increased risk for epileptic seizures, especially in the early phase of the disease; 2) the reduced ability to generate γ-oscillations; and 3) the increase in neuronal activity as measured by functional MRI. Homeostatic disinhibition may be the major mechanism that activates cognitive reserve. Modulating neuronal activity may therefore be a viable therapeutic strategy in AD that can complement existing anti-amyloid strategies. Specifically, enhancing endogenous glutamatergic synaptic transmission through increased co-agonist signaling or through positive allosteric modulation of metabotropic glutamatergic receptors appears as an attractive strategy. Alternatively, further reduction of GABAergic signaling may work as well, although care has to be taken to prevent epileptic seizures.

Original languageEnglish (US)
Pages (from-to)15-24
Number of pages10
JournalJournal of Alzheimer's Disease
Issue number1
StatePublished - 2011
Externally publishedYes


  • Alzheimer's disease
  • cognitive reserve
  • disinhibition
  • GABA
  • interneuron
  • neuronal activity

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology


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