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Myelinated axons have a distinct protein architecture essential for action potential propagation, neuronal communication, and maintaining cognitive function. Damage to myelinated axons, associated with cerebral hypoperfusion, contributes to age-related cognitive decline. We sought to determine early alterations in the protein architecture of myelinated axons and potential mechanisms after hypoperfusion. Using a mouse model of hypoperfusion, we assessed changes in proteins critical to the maintenance of paranodes, nodes of Ranvier, axon- glial integrity, axons, and myelin by confocal laser scanning microscopy. As early as 3 d after hypoperfusion, the paranodal septate-like junctions were damaged. This was marked by a progressive reduction of paranodal Neurofascin signal and a loss of septate-like junctions. Concurrent with paranodal disruption, there was a significant increase in nodal length, identified by Nav1.6 staining, with hypoperfusion. Disruption of axon- glial integrity was also determined after hypoperfusion by changes in the spatial distribution of myelin-associated glycoprotein staining. These nodal/paranodal changes were more pronounced after 1 month of hypoperfusion. In contrast, the nodal anchoring proteins AnkyrinG and Neurofascin 186 were unchanged and there were no overt changes in axonal and myelin integrity with hypoperfusion. A microarray analysis of white matter samples indicated that there were significant alterations in 129 genes. Subsequent analysis indicated alterations in biological pathways, including inflammatory responses, cytokinecytokine receptor interactions, blood vessel development, and cell proliferation processes. Our results demonstrate that hypoperfusion leads to a rapid disruption of key proteins critical to the stability of the axon- glial connection that is mediated by a diversity of molecular events. [ABSTRACT FROM AUTHOR]

Visual landmarks exert stimulus control over spatial behavior and the spatially tuned firing of place, head-direction, and grid cells in the rodent. However, the neural site of convergence for representations of landmarks and representations of space has yet to be identified. A potential site of plasticity underlying associations with landmarks is the postsubiculum. To test this, we blocked glutamatergic transmission in the rat postsubiculum with CNQX, or NMDA receptor-dependent plasticity with d-AP5. These infusions were sufficient to block evoked potentials from the lateral dorsal thalamus and long-term depression following tetanization of this input to the postsubiculum, respectively. In a second experiment, CNQX disrupted the stability of rat hippocampal place cell fields in a familiar environment. In a novel environment, blockade of plasticity with d-AP5 in the postsubiculum did not block the formation of a stable place field map following a 6 h delay. In a final behavioral experiment, postsubicular infusions of both compounds blocked object-location memory in the rat, but did not affect object recognition memory. These results suggest that the postsubiculum is necessary for the recognition of familiar environments, and that NMDA receptor-dependent plasticity in the postsubiculum is required for the formation of new object-place associations that support recognition memory. However, plasticity in the postsubiculum is not necessary for the formation of new spatial maps.