Decreased extrasynaptic δ‐GABAA receptors in PNN‐associated parvalbumin interneurons correlates with anxiety in APP and tau mouse models of Alzheimer's disease

Background Alzheimer's disease (AD) is associated with gradual memory loss and anxiety which affects ~75% of AD patients. This study investigated whether AD‐associated anxiety correlated with modulation of extrasynaptic δ‐subunit‐containing GABA A receptors (δ‐GABA A Rs) in experimental mouse models of AD. Experimental approach We combined behavioural experimental paradigms to measure cognition performance, and anxiety with neuroanatomy and molecular biology, using familial knock‐in (KI) mouse models of AD that harbour β‐amyloid (Aβ) precursor protein App ( App NL‐F ) with or without humanized microtubule‐associated protein tau ( MAPT ), age‐matched to wild‐type control mice at three different age windows. Results App NL‐F KI and App NL‐F / MAPT AD models showed a similar magnitude of cognitive decline and elevated magnitude of anxiety correlated with neuroinflammatory hallmarks, including triggering receptor expressed on myeloid cells 2 (TREM2), reactive astrocytes and activated microglia consistent with accumulation of Aβ, tau and down‐regulation of Wnt/β‐catenin signalling compared to aged‐matched WT controls. In both the CA1 region of the hippocampus and dentate gyrus, there was an age‐dependent decline in the expression of δ‐GABA A Rs selectively expressed in parvalbumin (PV)‐expressing interneurons, encapsulated by perineuronal nets (PNNs) in the AD mouse models compared to WT mice. In vivo positive allosteric modulation of the δ‐GABA A Rs, using a δ‐selective‐compound DS2, decreased the level of anxiety in the AD mouse models, which was correlated with reduced hallmarks of neuroinflammation, and ‘normalisation’ of the expression of δ‐GABA A Rs. Conclusions Our data show that the δ‐GABA A Rs could potentially be targeted for alleviating symptoms of anxiety, which would greatly improve the quality of life of AD individuals.