Sprouting has been studied extensively using morphological markers, but relatively little is known regarding the molecular and biochemical events which underlie the sprouting response. Moreover, due to the lack of suitable markers, it has been difficult to examine changes in the major hippocampal pathways in animal lesion models and in neurological disorders. We utilized two markers, obtained through molecular genetic analysis, to examine alterations in hippocampal circuits following partial deafferentation. SNAP-25, a neuronal specific protein, is located presynaptically in the perforant path, Schaffer collaterals, mossy fibers, and commissural/associational pathways. Selective destruction of CA3 pyramidal neurons, dentate gyrus granule cells, and entorhinal cortical neurons resulted in a loss of SNAP-25 immunoreactivity at the site of the axonal projections of the lesioned neurons. SNAP-25 immunoreactivity was maintained in projections to the lesioned region, and enhanced in areas adjacent to those deafferented by the lesions. Expression of SNAP 25 mRNA was increased in denervated regions, and in neurons which would be expected to participate in the sprouting response. Tubulin-alpha 1 is an mRNA which is expressed at high levels in the fetal brain during periods of neurite outgrowth, but at low levels in the adult brain. The expression of T alpha 1 mRNA was increased in the rat hippocampal neurons following entorhinal lesions, and in the human hippocampus in patients with Alzheimer's disease. These results demonstrate that sprouting in the CNS may result in the replay of developmental patterns of gene expression. Examination of SNAP-25 and T alpha 1 mRNA expression and of SNAP-25 immunoreactivity may be useful in investigating alterations in major hippocampal circuits in a variety of conditions such as learning, hypoxia, hypoglycemia, and also in neurological disorders such as temporal lobe epilepsy and Alzheimer's disease.