Neural cell adhesion molecules are known to be important in axon guidance and synapse formation in the developing brain. The embryonic form of neural cell adhesion molecule (eN-CAM) is reexpressed in the outer molecular layer (OML) of the dentate gyrus following entorhinal cortex (ERC) lesion. Ultrastructural analysis revealed localization of eN-CAM to the membrane of granule-cell dendritic membranes and occasionally axons within the denervated zone. Because eN-CAM is expressed rapidly (within 2 days) after ERC lesion, we were interested in the temporal sequence of expression. Denervated hippocampi (12, 15, 24, and 48 hours post-ERC lesion) were stained with anti-eN-CAM and processed for immunoelectron microscopy. At 12 hours, there was no evidence of staining for eN-CAM. By 15 hours after lesion, membranes of both dendrites and axons throughout the molecular layer exhibited moderate eN-CAM staining, and dendritic cytoplasm was heavily labeled. Twenty-four hours following lesion, plasma membrane staining of eN-CAM on both axons and dendrites had increased in intensity within the OML, whereas membrane eN-CAM staining was diminished in the inner molecular layer (IML), and the intradendritic cytoplasmic staining disappeared. By 48 hours after lesion, eN-CAM staining had disappeared from the IML but remained intense and widely distributed in the OML. These findings suggest a rapid transport of de novo synthesized protein. A generalized reaction appears to occur immediately following denervation, and eN-CAM i s up-regulated in the complete expanse of the dendritic membrane, despite the fact that only the OML is denervated. The newly up-regulated eN-CAM is rapidly withdrawn or disappears from the membrane in the (nondenervated) IML over the 24-48 hours postlesion. The brain rRpidly responds to injury at the cellular level in the denervated zone in preparation for renervation by axon sprouting. o 1994 Wiey-Liss, Inc.