DNA repair is one of the most essential systems for maintaining the inherited nucleotide sequence of genomic DNA over time. Repair of DNA damage would be particularly important in neurons, because these cells are among the longest-living cells in the body. MSH2 is one of the proteins which are involved in the recognition and repair of a specific type of DNA damage that is characterized by pair mismatches. We studied the distribution of MSH2 in rat brain by immunohistochemical analysis. We found the level of MSH2 expression in rat brain to be clearly heterogeneous. The highest intensity of staining was found in the pyramidal neurons of the hippocampus and in the entorhinal and frontoparietal cortices. Positive cells were observed in the substantia nigra pars compacta, in cerebellar granular and Purkinje cells, and in the motor neurons of the spinal cord. We investigated the possible modulation of MSH2 expression after injection of kainate. Systemic administration of kainate induces various behavioural alterations and a typical pattern of neuropathology, with cell death in the hippocampal pyramidal neurons of the CA3/CA4 fields. Kainate injection also resulted in a marked, dose-dependent increase of MSH2 immunoreactivity in the hippocampal neurons of the CA3/CA4 fields. The effect was specific, since no changes in immunoreactivity were detected in the dentate gyrus nor in other brain areas. In summary, our data suggest that a mismatch DNA repair system, of which MSH2 protein is a representative component, is heterogeneously expressed in the rat brain and specifically induced by an experimental paradigm of excitotoxicity.