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Highlights d Reactive astrocytes in SNpc produce excessive GABA via MAO-B in animal models of PD d Aberrant tonic inhibition causes reduced DA production in neurons and motor deficits d Dormant neurons are rescued by MAO-B inhibition or optogenetic neuronal activation

Highlights d Capsular infarct induces neuronal atrophy and reactive astrogliosis in motor cortex d Tonic GABA from reactive astrocytes suppresses neuronal glucose metabolism d Inhibition of MAO-B, the GABA-synthesizing enzyme, restores glucose metabolism d Combined therapy of MAO-B inhibitor and rehabilitation causes functional recovery

An ongoing pandemic of coronavirus disease 2019 (COVID-19) is now the greatest threat to global public health. Herbal medicines and their derived natural products have drawn much attention in the treatment of COVID-19, but the detailed mechanisms by which natural products inhibit SARS-CoV-2 have not been elucidated. Here, we show that platycodin D (PD), a triterpenoid saponin abundant in Platycodon grandiflorum (PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection routes via lysosome- and transmembrane protease serine 2 (TMPRSS2)-driven entry. Mechanistically, PD prevents host entry of SARS-CoV-2 by redistributing membrane cholesterol to prevent membrane fusion, which can be reinstated by treatment with a PD-encapsulating agent. Furthermore, the inhibitory effects of PD are recapitulated by the pharmacological inhibition or gene silencing of NPC1, which is mutated in patients with Niemann–Pick type C (NPC) displaying disrupted membrane cholesterol distribution. Finally, readily available local foods or herbal medicines containing PG root show similar inhibitory effects against SARS-CoV-2 infection. Our study proposes that PD is a potent natural product for preventing or treating COVID-19 and that briefly disrupting the distribution of membrane cholesterol is a potential novel therapeutic strategy for SARS-CoV-2 infection.

Graphical Abstract Highlights d Hippocampal astrocytic m-opioid receptor (MOR) activation drives conditioned place preference (CPP) d Astrocytic MOR activation enhances synaptic plasticity at the Schaffer collateral pathway d Chemogenetic activation of astrocytic Gi-DREADD recapitulates MOR-mediated LTP and CPP SUMMARYThe underlying mechanisms of how positive emotional valence (e.g., pleasure) causes preference of an associated context is poorly understood. Here, we show that activation of astrocytic m-opioid receptor (MOR) drives conditioned place preference (CPP) by means of specific modulation of astrocytic MOR, an exemplar endogenous Gi protein-coupled receptor (Gi-GPCR), in the CA1 hippocampus. Long-term potentiation (LTP) induced by a subthreshold stimulation with the activation of astrocytic MOR at the Schaffer collateral pathway accounts for the memory acquisition to induce CPP. This astrocytic MOR-mediated LTP induction is dependent on astrocytic glutamate released upon activation of the astrocytic MOR and the consequent activation of the presynaptic mGluR1. The astrocytic MOR-dependent LTP and CPP were recapitulated by a chemogenetic activation of astrocyte-specifically expressed Gi-DREADD hM4Di. Our study reveals that the transduction of inhibitory Gisignaling into augmented excitatory synaptic transmission through astrocytic glutamate is critical for the acquisition of contextual memory for CPP.

In the originally published version of this article, the author name Jung Moo Lee was spelled incorrectly. This has now been corrected online.

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