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. 2024 Oct;181(20):3944-3975.
doi: 10.1111/bph.16441. Epub 2024 Jun 17.

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

Weicong Zhang  1 , Tiansheng Liu  1 , Jialin Li  1 , Jaijeet Singh  1 , Andi Chan  1 , Anam Islam  1 , Alexandra Petrache  1 , Yunan Peng  1 , Kirsten Harvey  1 , Afia B Ali  1
Affiliations
Free article

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

Weicong Zhang et al. Br J Pharmacol. 2024 Oct.
Free article

Abstract

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 GABAA receptors (δ-GABAARs) 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 (AppNL-F) with or without humanized microtubule-associated protein tau (MAPT), age-matched to wild-type control mice at three different age windows.

Results: AppNL-F KI and AppNL-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-GABAARs 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-GABAARs, 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-GABAARs.

Conclusions: Our data show that the δ-GABAARs could potentially be targeted for alleviating symptoms of anxiety, which would greatly improve the quality of life of AD individuals.

Keywords: Alzheimer's disease; extra‐synaptic GABAA receptors; hippocampus; parvalbumin interneurons; perineuronal nets.

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