Dural mast cells subjacent to the craniectomy became activated (degranulated) concomitant with (1) decreased histamine in dura mater subjacent to the craniectomy; (2) increased histamine in the subjacent cerebral cortex; and (3) extravasation of Evans blue-albumin which stained the subjacent cerebral cortex, indicating a localized breakdown of the blood-brain barrier. Similar results were observed in mice after scoring the parietal bone surface and, additionally, pretreatment with the histamine H(2)-receptor antagonist zolantadine (1 h before injury) dose-dependently inhibited extravasation of Evans blue-albumin. We conclude that even a minor grazing injury of the skull, in the absence of penetrating brain injury or concussion, can activate dural mast cells and elevate cortical histamine, a novel mechanism with potential contributions to neurotraumatic complications arising from a relatively minor or grazing head wound.
Anterograde fast axonal transport (FAxT) maintains synaptic function and provides materials necessary for neuronal survival. Localized changes in FAxT are associated with a variety of central nervous system (CNS) neuropathies, where they may contribute to inappropriate remodeling, a process more appropriately involved in synaptic plasticity and development. In some cases, developmental remodeling is regulated by localized secretion of endothelins (ETs), neuroinflammatory peptides that are also pathologically elevated in cases of neurologic disease, CNS injury, or ischemia. To investigate the potential role of ETs in these processes, we decided to test whether locally elevated endothelin-1 (ET-1) modulates FAxT in adult CNS tissues. We used the established in vivo rat optic nerve model and a novel ex vivo rat hippocampal slice model to test this hypothesis. In vivo, exogenously elevated vitreal ET-1 significantly affected protein composition of FAxT-cargos as well as the abundance and peak delivery times for metabolically-labeled proteins that were transported into the optic nerve. Proteins with molecular weights of 139, 118, 89, 80, 64, 59, 51, 45, 42, 37, and 25 kDa were evaluated at injection-sacrifice intervals (ISIs) of 24, 28, 32, and 36 hr. In acute hippocampal slices maintained on nonvascular supplies of glucose and oxygen, ET-1 significantly decreased the distance traveled along the Schaffer collateral tract by nonmetabolically-labeled lipid rafts at 5 and 10 min after pulse-labeling. In both models, ET-1 significantly affected transport or targeted delivery of FaxT-cargos, suggesting that ET-1 has the potential to modulate FAxT in adult CNS tissues.
Polycystin-1 (PC-1) has been identified as critical to development of the nervous system, but the significance of PC-1 expression in neurons remains undefined, and little is known of its roles outside the kidney, where mutation results in autosomal dominant polycystic kidney disease (ADPKD). In kidney, PC-1 interacts with cadherins, catenins, and its cognate calcium channel polycystin-2 (PC-2), which in turn interacts with a number of actin-regulatory proteins. Because some of the proteins that interact with PC-1 in kidney also participate in synaptic remodeling and plasticity in the hippocampus, we decided to test PC-1's potential to interact with a recently discovered type of plasticity-associated protein (homer 1a/Vesl-1S) in postnatal mouse hippocampus. Homer 1a/Vesl-1S is an activity-induced protein believed to participate in synaptic remodeling/plasticity responses to temporal lobe seizure and learning. Here we report the following. 1) PC-1 contains a homer-binding motif (PPxxF), which lies within its purported cytoplasmic domain. 2) Immunoreactivity for PC-1 (PC-1-ir) is highly colocalized with homer 1a immunoreactivity (H1a-ir) in primary cultured hippocampal neurons. 3) PC-1-ir and H1a-ir are present and appear to be colocalized in mouse hippocampus but not cortex on postnatal day 2 (P2), when higher frequencies of spontaneous activity are normal for hippocampus compared with cortex. 4) An endogenous PC-1-ir band with the correct size for the reported C-terminal G-protein-sensitive domain cleavage product of PC-1 (approximately 150 kDa) coimmunoprecipitates with endogenous homer 1/Vesl-1 proteins from mouse brain, suggesting that PC-1 can interact with homer 1/Vesl-1 proteins in postnatal hippocampal neurons.
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