Background and Purpose As the only ionotropic receptor in 5-HT receptor family, 5-HT3 receptor (5-HT3R) involves in psychiatric disorders and its modulators have potential therapeutic effects for cognitive impairment in these disorders. However, it remains unclear how 5-HT3Rs shape synaptic plasticity for memory function. Experimental Approach Extracellular as well as whole-cell recordings were used to monitor hippocampal long-term potentiation (LTP) and synaptic transmission in hippocampal slices from 5-HT3AR knock-out or 5-HT3AR-GFP mice. Immunocytochemistry, qRT-PCR and Western blot were used to measure receptor expression. We also assessed hippocampal dependent cognition and memory using the Morris water maze (MWM) and novel object recognition. Key Results We found that 5-HT3R dysfunction impaired hippocampal LTP in Schaffer collateral (SC)-CA1 pathway in hippocampal slices by facilitating GABAergic inputs in pyramidal cells. This effect was dependent on 5-HT3Rs on axon-terminals. It resulted from reduced expression and function of cannabinoid receptor 1 (CB1R) co-localized with 5-HT3Rs on axon terminals, which led to diminishment of tonic inhibition of GABA release by CB1Rs. Inhibition of CB1Rs mimicked the facilitation of GABAergic transmission by 5-HT3R disruption. Consequently, mice with hippocampal 5-HT3R disruption exhibited impaired spatial memory in Morris water maze tasks. Conclusion and Implications These results suggest that 5-HT3Rs are crucial in enabling hippocampal synaptic plasticity via a novel CB1R-GABA_A-dependent pathway to regulate spatial memory.

Background: The effect of multiple mutations in CYP2C19, PON1 and ABCB1 genes on the effectiveness and safety of dual antiplatelet therapy after percutaneous coronary intervention remains unclear. ... Plain language summary The effects of different combinations of mutations in the genes CYP2C19, PON1 and ABCB1 on the effectiveness and safety of dual antiplatelet therapy in patients who undergo p... Tweetable abstract Multiple genetic mutations influence platelet response and thrombosis risk with clopidogrel and aspirin after percutaneous coronary intervention.

Warfarin, with its narrow therapeutic range, requires the understanding of various influencing factors for personalized medication. Vascular senescence, marked by vascular stiffening and endothelial dysfunction, has an unclear effect on the efficacy and safety of warfarin. Based on previous studies, we hypothesized that vascular senescence increases the risk of bleeding during warfarin therapy. This study aimed to explore these effects using animal models and clinical cohorts. We established rat models of vascular senescence and calcification using d-galactose (D-Gal), vitamin D and nicotine (VDN). After validating the models, we examined changes in the International Normalized Ratio (INR) at fixed warfarin doses (0.20 and 0.35 mg/kg). We found that vascular senescence caused significantly elevated INR values and increasd bleeding risk. In the prospective clinical cohort study(NCT06428110), hospitalized warfarin patients with standard dose adjustments were divided into vascular senescence and control groups based on ultrasound and Computed Tomography (CT) diagnosis. Using propensity score matching (PSM) to exclude the influence of confounding factors, we found that the vascular senescence group had lower steady-state warfarin doses and larger dose adjustments, with a higher probability of INR exceeding the therapeutic range. The vascular senescence group tended to experience more bleeding or thromboembolic/ischemic events during one year of follow-up, while there was no statistical difference. In conclusion, vascular senescence leads to unstable INR values and increases higher bleeding risk during warfarin therapy, highlighting the importance of considering vascular senescence in future precision warfarin therapies. Significance Statement Many factors influence warfarin efficacy, however, the effect of vascular senescence remains unclear. This study aimed to investigate the effects of vascular senescence on the efficacy and safety of warfarin. Through both rat models and clinical cohort studies, our findings indicated that vascular senescence may compromise the stability of warfarin, presenting challenges in maintaining its efficacy and safety.

Background:Different combinations of multiple mutations of CYP2C19, PON1and ABCB1 for the efficiency and safety of Clopidogrel in patients undergoing percutaneous coronary intervention (PCI) remain unclear.Methods: 263 Chinese Han patients receiving 75mg Clopidogrel and 100mg Aspirin every day for 12 months after PCI were enrolled in this study. ADP-induced platelet aggregation rates, thrombosis and bleeding risk are used to compare the Clopidogrel response among the combined genetic mutation. Results: Our study demonstrated that multiple genetic mutations are very common in patients receiving Clopidogrel and Aspirin after PCI.Patients who have high ADP-induced platelet aggregation rate with more mutations of CYP2C19, PON1 and ABCB1. Patients with full mutations of CYP2C19, PON1 and ABCB1 have highest risk of thrombosis and lowest risk of bleeding in patients receiving clopidogrel and aspirin with one-year follow-up duration.Conclusions:We summarized multiple genetic polymorphism influences platelet reactivity, bleeding and thrombosis risk to Clopidogrel after percutaneous coronary intervention.