Although its effect on cognitive functions has been one of the hot topics in the present neuroscience research, the mechanism of epilepsy related cognitive impairment is not clearly revealed. Intracellular Ca(2+) plays an important role in regulating many cellular functions including learning and memory, this experiment was therefore conducted, in which, we observed the behaviors of chronic epileptic rats kindled by pentylenetetrazol (PTZ) through Morris water maze (MWM), examined the concentration of intracellular free calcium ([Ca(2+)](i)) with flow cytometry, and tested the expression of calcium/calmodulin-dependent protein kinase IIalpha (CaMKII(alpha)) and cAMP-response element binding protein (CREB) in hippocampus of those rats using western blot and reverse transcription-polymerase chain reaction (RT-PCR). The results demonstrate impaired ability of spatial learning and memory, increased concentration of [Ca(2+)](i), decreased expression levels of total CaMKII(alpha), phosphorylated CaMKII(alpha) (P-CaMKII(alpha)) and phosphorylated CREB (P-CREB) and decreased levels of CaMKII(alpha) mRNA and CREB mRNA of the epileptic rats compared with the normal control rats. Moreover, Nimodipine, an inhibitor of voltage-dependent L-type Ca(2+) channels (VDCCs), reduced the Racine's stage, improved the ability of spatial learning and memory, reversed the effect of Ca(2+) influx and expression levels of CaMKII(alpha) and CREB of the epileptic rats. We concluded that Ca(2+) influx, CaMKII(alpha) and CREB expression levels in hippocampus of chronic epileptic rats may be related with their impaired spatial learning and memory.