Antibodies to antigen PSD-95, a neuronal protein present only in postsynaptic densities (PSDs), have been used to follow immunohistochemically the loss and recovery of PSDs after selective deafferentation of both the hippocampal formation and the lateral septal nucleus of the rat. Three days after unilateral entorhinal ablation, densitometry of brain tissue sections stained by the peroxidase-antiperoxidase (PAP) method showed a decrease of about 25% in the outer 2/3 of the ipsilateral dentate gyrus molecular layer (ML), whereas staining in the inner 1/3 of the same ML layer actually increased about 16%. The intensely staining inner 1/3 of the deafferented ML expanded over time so that by 30 days postlesion the expansion had reached 60-70% of the ML. In the lateral septal nucleus, unilateral fimbria transection did not change either the pattern of anti-PSD PAP staining or that of [125I]protein A binding as revealed by autoradiography or by microdissection of the lateral septal nuclei to determine bound radioactivity by gamma-counting. Bilateral intraventricular injection of kainic acid to destroy area CA3 of the ipsilateral hippocampus caused very little loss of anti-PSD stain in the dentate gyrus ML, but decreased by 45% and 34% the intensity of stain in stratum radiatum and stratum oriens of the hippocampus, respectively. However, bilateral injections of doses of kainate high enough to destroy areas CA3, CA4 and part of CA1, caused 53% loss of stain in the inner 1/3 of the dentate gyrus ML. Recovery from the PSD loss caused by kainate in area CA1 was slow, only 67-81% of control by 90 days post-lesion. The immunohistochemical results in dentate gyrus and septum corresponded closely with quantitative data obtained by electron microscopy. Therefore, the response of PSDs to the loss of their presynaptic counterpart appears to depend on the overall extent of deafferentation of the neuron, the zone of the dendritic tree where deafferentation occurs and, perhaps, other specific features of the target cells.