Antineoplastic drugs such as oxaliplatin(OXA)often induce memory and emotional deficits.At present,the mechanisms underlying these side-effects are not fully understood,and no effective treatment is available.Here,we show that the short-term memory deficits and anxiety-like and depression-like behaviors induced by intraperi-toneal injections of OXA(4 mg/kg per day for 5 consec-utive days)were accompanied by synaptic dysfunction and downregulation of the NR2B subunit of N-methyl-D-aspartate receptors in the hippocampus,which is critically involved in memory and emotion.The OXA-induced behavioral and synaptic changes were prevented by chronic oral administration of magnesium-L-threonate(L-TAMS,604 mg/kg per day,from 2 days before until the end of experiments).We found that OXA injections significantly reduced the free Mg2+in serum and cerebrospinal fluid(from～0.8 mmol/L to～0.6 mmol/L).The Mg2+defi-ciency(0.6 mmol/L)upregulated tumor necrosis factor(TNF-a)and phospho-p65(p-p65),an active form of nuclear factor-kappaB(NF-kB),and downregulated the NR2B subunit in cultured hippocampal slices.Oral L-TAMS prevented the OXA-induced upregulation of TNF-a and p-p65,as well as microglial activation in the hippocampus and the medial prefrontal cortex.Finally,similar to oral L-TAMS,intracerebroventricular injection of PDTC,an NF-xB inhibitor,also prevented the OXA-induced memory/emotional deficits and the changes in TNF-a,p-p65,and microglia.Taken together,the activa-tion of TNF-o/NF-xB signaling resulting from reduced brain Mg2+is responsible for the memory/emotional deficits induced by OXA.Chronic oral L-TAMS may be a novel approach to treating chemotherapy-induced mem-ory/emotional deficits.