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Publication Detail
Aberrant Excitatory-Inhibitory Synaptic Mechanisms in Entorhinal Cortex Microcircuits during the Pathogenesis of Alzheimer’s disease
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Petrache AL, Rajulawalla A, Shi A, Wetzel A, Saito T, Saido TC, Harvey K, Ali A
  • Publisher:
    Oxford University Press (OUP)
  • Publication date:
  • Journal:
    Cerebral Cortex
  • Status:
    Published online
  • Print ISSN:
  • Language:
  • Keywords:
    Alzheimer’s disease, Interneurons, GABA_{A}, Wnt signalling, Synapse
Synaptic dysfunction is widely proposed as an initial insult leading to the neurodegeneration observed in Alzheimer's disease (AD). We hypothesise that the initial insult originates in the lateral entorhinal cortex (LEC) due to deficits in key interneuronal functions and synaptic signalling mechanisms, in particular, Wnt (Wingless/integrated). To investigate this hypothesis, we utilized the first knock-in mouse model of AD (App^{NLF/NL-F}}, expressing a mutant form of human amyloid-β (Aβ) precursor protein. This model shows an age-dependent accumulation of Aβ, neuroinflammation, and neurodegeneration. Prior to the typical AD pathology, we showed a decrease in canonical Wnt signalling activity first affecting the LEC in combination with synaptic hyperexcitation and severely disrupted excitatory-inhibitory inputs onto principal cells. This synaptic imbalance was consistent with a reduction in the number of parvalbumin-containing (PV) interneurons, and a reduction in the somatic inhibitory axon terminals in the LEC compared to other cortical regions. However, targeting GABAA receptors on PV cells using allosteric modulators, diazepam, zolpidem or a non-benzodiazepine, L-838,417 (modulator of α2/3 subunit-containing GABAA receptors), restored the excitatory-inhibitory imbalance observed at principal cells in the LEC. These data support our hypothesis, providing a rationale for targeting the synaptic imbalance in the LEC for early stage therapeutic intervention to prevent neurodegeneration in AD.
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