Febrile seizure (FS) remains the most common childhood neurological emergency. Although many studies have been done, controversy exists as to whether these seizures are associated with a significant risk for cognitive impairment. The aim of our study is to check whether there is a spatial learning and memory deficit in the experimental FS rats using a heated-air FS paradigm and to determine the possible molecular mechanism of cognitive impairment. On days 10 to 12 postpartum, the male rat pups were subjected to one, three, or nine episodes of brief hyperthermia-induced seizures (HS). At adolescence and adulthood, the rats subjected to three, or nine episodes of HS had significant deficits in spatial learning and memory tested by Morris water maze. At adulthood, no apparent hippocampal neuronal loss was found in any HS group, but the seizure threshold to flurothyl was decreased significantly in the rats subjected to nine episodes of HS. In the rats subjected to three, or nine episodes of HS, the Western immunoblotting showed that there was a significant translocation of Ca2+ -calmodulin stimulated protein kinase II (CaMKII) from the postsynaptic density to the cytosol. In the postsynaptic density the phosphorylation of CaMKII alpha Thr(286) was reduced significantly, but the phosphorylation of CaMKIIa Thr(305) was increased significantly. Our study showed early-life brief but recurrent HS caused long-term cognitive impairment and CaMKIIa was involved in carrying forward the signal resulting from HS. The change of the phosphorylative level in Thr(286) and Thr(305) sites of CaMKIIa may underlie the molecular mechanism for the HS related cognitive impairment. (c) 2014 Elsevier B.V. All rights reserved.