Abstract Synaptosomal-associated protein, 25 kD, (SNAP-25) is a novel protein containing a possible transition metal binding site and encoded by a neuronal-specific mRNA. We examined the distribution of SNAP-25 mRNA and protein in the hippocampal formation of the adult rat following kainic acid, colchicine, and entorhinal lesions. The results show that destruction of granule cells of the dentate gyrus and CA3 pyramidal cells did not diminish SNAP-25 immunoreactivity in the dendritic fields of these cells. In contrast, lesioned neurons exhibited an extensive loss of immunoreactivity at the site of their axonal projections. These results support the identification of SNAP-25 as a novel presynaptic protein. In addition, SNAP-25 immunoreactivity was increased in afferent fibers which project to areas adjacent to the deafferented region, and expression of SNAP-25 mRNA was increased in neurons deafferented by the lesion. Examination of SNAP-25 immunoreactivity and mRNA expression may provide a useful marker of major hippocampal pathways and of axonal plasticity in neurological disorders such as Alzheimer's disease and temporal lobe epilepsy.