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SELECTIVE VULNERABILITY OF HIPPOCAMPAL PRINCIPAL CELLS ASSOCIATED WITH EXTRASYNAPTIC Δ-GABAA RECEPTOR DYSREGULATION IN ALZHEIMER’S DISEASE
Andi Chanand 6 co-authors
University College London
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS05-09AM-149
Presentation
Date TBA
Board: PS05-09AM-149
Event Information
Poster Board
PS05-09AM-149
Poster
View posterAbstract
Disruption of the excitatory-inhibitory balance in Alzheimer’s disease (AD) may reflect reduced inhibitory control of principal excitatory cells, driving hyperexcitability. We previously showed that a knock-in AD model exhibits cognitive decline and anxiety-like behaviour, consistent with impaired GABAergic regulation. Extrasynaptic δ-containing GABAA receptors (δ-GABAARs) regulate principal cell excitability and may be disrupted across hippocampal subregions. We investigated whether δ-GABAAR expression is altered with disease progression and whether receptor modulation restores expression and reduces anxiety-like behaviour.
Behavioural analyses were combined with neurochemical, pharmacological, and confocal microscopy approaches in young and aged APPNL-F/NL-F and wild-type mice, aged 2 to 4 or 12 to 16 months. δ-GABAARs and CaMKIIα pyramidal or granule cell expression and colocalisation were examined in the hippocampal CA1 and dentate gyrus (DG) regions with or without 7 days of intraperitoneal administration (10 mg/kg) of the novel δ-GABAAR selective positive allosteric modulator (PAM) MDI-117289 or saline vehicle.
Behavioural analyses were combined with neurochemical, pharmacological, and confocal microscopy approaches in young and aged APPNL-F/NL-F and wild-type mice, aged 2 to 4 or 12 to 16 months. δ-GABAARs and CaMKIIα pyramidal or granule cell expression and colocalisation were examined in the hippocampal CA1 and dentate gyrus (DG) regions with or without 7 days of intraperitoneal administration (10 mg/kg) of the novel δ-GABAAR selective positive allosteric modulator (PAM) MDI-117289 or saline vehicle.
Z-stack confocal imaging revealed an age dependent reduction in δ-GABAAR expression in the AD model, in addition to demonstrating brain region specific vulnerability. The most pronounced decrease was observed in the CA1, with a more modest reduction in the DG. δ-GABAAR colocalisation with CaMKIIα positive excitatory neurons followed a similar pattern. Treatment with MDI-117289 reduced anxiety and restored δ-GABAARs expression across hippocampal subregions in AD mice.
These findings identify selective impairment of tonic inhibition in early affected hippocampal circuits and suggest that δ-GABAARs modulation with MDI-117289 may alleviate anxiety-like behaviour while restoring inhibitory control and limiting excitotoxicity in AD.
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