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Our previous works demonstrated that β2-microglobulin (β2m), a systemic pro-aging factor, induce depressive-like behaviors. Hydrogen sulfide (H 2 S) is identified as a potential target for treatment of depression. The aim of the present work is to explore whether H 2 S antagonizes β2m-induced depressive-like behaviors and the underlying mechanisms. The depressive-like behaviors were detected using the novelty suppressed feeding test (NSFT), tail suspension test (TST), forced swimming test (FST) and open field test (OFT). The expressions of Warburg-related proteins, including hexokinase II (HK II), pyruvate kinase M2 (PKM2), Lactate dehydrogenase A (LDHA), pyruvate dehydrogenase (PDH) and pyruvate dehydrogenase kinase 1(PDK1), and synaptic plasticity-related proteins, including postsynaptic density protein 95 (PSD95) and synaptophysin1 (SYN1), were determined by western blotting. we found that NaHS (the donor of H 2 S) attenuated the depressive-like behaviors in the β2m-exposed rats, as judged by NSFT, TST, FST, and OFT. We also demonstrated that NaHS enhanced the synaptic plasticity, as evidenced by the upregulations of PSD95 and SYN1 expressions in the hippocampus of β2m-exposed rats. Furthermore, NaHS improved the Warburg effect in the hippocampus of β2m-exposed rats, as evidenced by the upregulations of HK II, PKM2, LDHA and PDK1 expressions, and the downregulation of PDH expression. H 2 S prevents β2m-induced depressive-like behaviors, which is involved in improvement of hippocampal synaptic plasticity as a result of enhancement of hippocampal Warburg effect. • H 2 S attenuates β2m-induced depressive-like behaviour. • H 2 S improves synaptic plasticity in the hippocampus of β2m-exposed rat. • H 2 S enhances Warburg effect in the hippocampus of β2m-exposed rat. • H 2 S prevents β2m-induced depression via Warburg effect- synaptic plasticity axis. [ABSTRACT FROM AUTHOR]

Highlights: [•] Exposure of rats to homocysteine (Hcy) leads to learning and memory dysfunctions. [•] Hcy decreases the generation of endogenous H2S in the hippocampus of rats. [•] Hcy up-regulates the endoplasmic reticulum (ER) stress in the hippocampus of rats. [•] Disturbed H2S formation and ER stress involve in Hcy-caused memory disorder. [ABSTRACT FROM AUTHOR]