Non-cardiomyocytes in the heart in embryo development, health, and disease, a single-cell perspective.

Recent single-cell atlases of the heart gave unprecedented details about the diversity of cell types and states during heart development in health and disease conditions. Beyond a profiling tool, researchers also use single-cell analyses to dissect the mechanism of diseases in animal models. The new knowledge from these studies revealed that beating cardiomyocytes account for less than 50% of the total heart cell population. In contrast, non-cardiomyocytes (NCMs), such as cardiac fibroblasts, endothelial cells, and immune cells, make up the remaining proportion and have indispensable roles in structural support, homeostasis maintenance, and injury repair of the heart. In this review, we categorize the composition and characteristics of NCMs from the latest single-cell studies of the heart in various contexts and compare the findings from both human samples and mouse models. This information will enrich our understanding of the cellular basis of heart development and diseases and provide insights into the potential therapeutic targets in NCMs to repair the heart.

Reversible GABAergic dysfunction involved in hippocampal hyperactivity predicts early-stage Alzheimer disease in a mouse model.

BACKGROUND: Neuronal hyperactivity related to ß-amyloid (Aß) is considered an early warning sign of Alzheimer disease (AD). Although increasing evidence supports this opinion, the underlying mechanisms are still unknown. METHODS: Here, we recorded whole-cell synaptic currents and membrane potentials using patch clamping of acute hippocampal slices from human amyloid precursor protein (APP)/presenilin-1 transgenic (5XFAD) mice and their wild-type littermates. Biochemical methods, electron microscopic imaging, behavioral tests, and intraventricular drug delivery applied with osmotic pumps were used in this study. RESULTS: We confirmed hyperactivity of hippocampal CA1 pyramidal neurons in 5XFAD mice using whole-cell electrophysiological recording at 2.5 months old, when local Aß-positive plaques had not developed and only mild cognitive dysfunction occurred. We further discovered attenuated inhibitory postsynaptic currents and unchanged excitatory postsynaptic currents in CA1 pyramidal neurons, in which the intrinsic excitability was unchanged. Moreover, the density of both γ-aminobutyric acid A (GABAA) receptor subunits, α1 and γ2, was reduced in synapses of the hippocampus in transgenic mice. Intriguingly, early intervention with the GABAA receptor agonist gaboxadol reversed the hippocampal hyperactivity and modestly ameliorated cognitive performance in 5XFAD mice under our experimental conditions. CONCLUSIONS: Inhibitory postsynaptic disruption critically contributes to abnormalities in the hippocampal network and cognition in 5XFAD mice and possibly in AD. Therefore, strengthening the GABAergic system could be a promising therapy for AD in the early stages.