Hippocampal Warburg Effect Mediates The Antidepressant-like Role Of Hydrogen Sulfide Via Improving Hippocampal Synaptic Plasticity

?Background and Objective?Depression is a common mental disorder,which is closely related to the damage of hippocampal synaptic plasticity induced by chronic stress.As a novel neuromodulator,Hydrogen sulfide?H₂S?plays an important role in regulating synaptic plasticity.Our previous works have shown that H₂SsignificantlyattenuatesChronicunpredictablemildstress?CUMS?-induced depressive-like behaviors,but the specific mechanism remains unclear.Warburg effect,namely aerobic glycolysis,acts a crucial role in promoting hippocampal synaptic plasticity.Therefore,the present work was to explore the antidepressant mechanism of H₂S from the new perspective of hippocampal Warburg effect and synaptic plasticity.?Methods?1.CUMS was used to established chronic stress depression model;2.The degree of depression was evaluated by sucrose preference tests?SPT?,elevated plus-maze test?EPMT?,and tail suspension test?TST?;3.The expressions of synaptic plasticity-related proteins?PSD95 and Syn-1?were detected by western blotting and immunohistochemical;4.Ultrastructure and density of hippocampal synapses were detected by transmission electron microscopy?TEM?;5.The expressions of warburg effect-related proteins?HK2,PKM2,PDK1,LDHA and PDH?in the hippocampus of rats were detected by Western blotting;6.Production of lactate in hippocampus was detected using Lactate Assay Kit.?Results?1.H₂S ameliorates the disorder of hippocampal synaptic plasticity in the CUMS-exposed rats The expressions of the synaptic plasticity-related proteins,PSD95 and Syn-1,were significantly decreased,the density of synapses,the length of synaptic activity area,and the thickness of PSD were significantly decreased,as well as the width of synaptic gap was increased,in the hippocampus?CA1 and CA3?of CUMS-exposed rats,which indicated that chronic stress induces hippocampal synaptic plasticity disorder.While NaHS?30,100?mol/kg,i.p.?upregulated the expressions of PSD95 and Syn-1,significantly increased the density of synapses,the length of synaptic activity area,and the thickness of PSD,as well as decreased the width of synaptic gap,in the hippocampus of CUMS-exposed rats,which indicated that H₂S ameliorates the disorder of hippocampal synaptic plasticity in the CUMS-exposed rats.2.H₂S promotes the hippocampal warburg effect in the CUMS-exposed rats The expressions of HK2,PKM2,PDK1,and LDHA were significantly decreased,the expression of PDH was increased,and the production of lactate was decreased in the hippocampal CUMS-exposed rats,which indicated that chronic stress induces disorder of hippocampal warburg effect.While NaHS?30,100?mol/kg,i.p.?upregulated the expressions of HK2,PKM2,PDK1 and LDHA,downregulated the expression of PDH,and enhanced the production of lactate in the hippocampal CUMS-exposed rats,which indicated that H₂S promotes the warburg effect in the hippocampus of CUMS-exposed rats.3.2-dexyglucose?2DG?,an inhibitor of warburg effect,abolished the promoting role of H₂S in the hippocampal warburg effect of CUMS rats2DG?100 mg/kg,i.p.?significantly decreased the expressions of HK2,PKM2,PDK1 and LDHA,increased the expression of PDH,and suppressed the production of lactate in the hippocampus of co-treated with CUMS and NaHS rats,indicated that 2DG alleviates H₂S-enhanced warburg effect in the hippocampus of CUMS-exposed rats.4.2DG reverses the protection of H₂S against CUMS-induced hippocampal synaptic plasticity disorder2DG?100 mg/kg,i.p.?downregulated the expressions of PSD95 and Syn-1,decreased the density of synapses,the length of synaptic activity area,and the thickness of PSD,as well as increased the width of synaptic gap,in the hippocampus of CUMS cotreated with NaHS rats,indicated that blockade of hippocampal warburg effect reverses the protection effect of H₂S against CUMS-induced hippocampal synaptic plasticity disorder.5.2DG reverses the protection of H₂S against CUMS-induced depressive-like behaviors2DG?100 mg/kg,i.p.?decreased the sucrose preference in the SPT,reduced the percentage of entries into the open arms and the time spent in open arms?while the number of total arm entries was no change?in the EPMT,increased the immobility time in the TST,in the co-treated with CUMS and NaHS rats,which indicated that inhibition of hippocampal warburg effect reverses the protection of H₂S against CUMS-induced depressive-like behaviors.?Conclusion?Hippocampal warburg effect mediates antidepressant-like role of H₂S via improving hippocampal synaptic plasticity.