Background Intense exercise can cause injury and apoptosis,but few studies have reported its effect on the central nervous system (CNS).The initial reason for hippocampus injury is the excitotoxicity of glutamate and calcium overload.Intracellular free Ca2+ ([Ca2+]i) overload may trigger the apoptosis pathway and neuron damage.The aim of this study was to investigate whether intense exercise could cause hippocampus apoptosis and neuron damage and then to determine which pathway was activated by this apoptosis.Methods We used one bout of swimming exhaustion rats as models.Intracellular [Ca2+]i was measured to estimate the calcium overload by Fura-2/AM immediately after exhaustion; glial fibrillary acidic protein (GFAP) and synaptophysin (SYP)immunofluorescence were performed for estimating astrocyte activation and synapse plasticity 24 hours after exhaustion.Apoptosis cells were displayed using dUTP nick end labelling (TUNEL) stain; endoplasmic reticulum (ER) stress-induced apoptosis pathway and mitochondrial apoptosis pathway were synchronously detected by West blotting.Results An increasing level of intracellular [Ca2+]i (P ＜0.01) was found in the hippocampus immediately after exhaustion.GFAP and SYP immunofluorescence showed that the astrocytes are activated,and the synapse plasticity collapsed significantly 24 hours after exhaustion.TUNEL stain showed that the number of apoptosis cells were notably raised (P ＜0.01); West blotting of the apoptosis pathway showed increasing levels of caspase-3 cleavage (P ＜0.01),Bax (P ＜0.01),caspase-12 cleavage (P ＜0.01),C/EBP-homologous protein (CHOP) (P ＜0.01),and phospho-Junaminoterminal kinases (p-JNK; P ＜0.01) and decreasing level of Bcl-2 (P ＜0.01).Our results proved that exhaustion can induce hippocampus injury and apoptosis by [Ca2+]i overload,with collapsed synaptic plasticity as the injury patt and ER stress-induced apoptosis as the activated pathway.Conclusion Intense exercise can cause excessive apoptosis and synapse plasticity damage in the hippocampus with [Ca2+]i overload as the initial reason,and thus provides leads for therapeutic interventions in the brain health of athletes.