Neuroscience
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Tissue-type Plasminogen Activator Induces Synaptic Vesicle Endocytosis in Cerebral Cortical Neurons.
The release of the serine proteinase tissue-type plasminogen activator (tPA) from the presynaptic terminal of cerebral cortical neurons plays a central role in the development of synaptic plasticity, adaptation to metabolic stress and neuronal survival. Our earlier studies indicate that by inducing the recruitment of the cytoskeletal protein βII-spectrin and voltage-gated calcium channels to the active zone, tPA promotes Ca(2+)-dependent translocation of synaptic vesicles (SVs) to the synaptic release site where they release their load of neurotransmitters into the synaptic cleft. Here we used a combination of in vivo and in vitro experiments to investigate whether this effect leads to depletion of SVs in the presynaptic terminal. ⋯ We report that this tPA-induced sequence of events leads to the association of newly formed SVs with F-actin clusters in the endocytic zone. In summary, the data presented here indicate that following the exocytotic release of neurotransmitters tPA activates the mechanism whereby SVs are retrieved from the presynaptic membrane and endocytosed to replenish the pool of vesicles available for a new cycle of exocytosis. Together, these results indicate that in murine cerebral cortical neurons tPA plays a central role coupling SVs exocytosis and endocytosis.
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We explored the changes in multi-finger synergies in patients after a single cortical stroke with mild motor impairments. We hypothesized that both synergy indices and anticipatory synergy adjustments prior to the initiation of a self-paced quick action would be diminished in the patients compared to age-matched controls. The patients with history of cortical stroke, and age-matched controls (n=12 in each group) performed one-finger and multi-finger accurate force production tasks involving both steady-state and quick force pulse production. ⋯ In contrast, a drop in the synergy index prior to the force pulse generation was significantly delayed in the stroke patients. Our results show that mild cortical stroke leads to no significant changes in multifinger synergies, but there is impairment in feed-forward adjustments of the synergies prior to a quick action, a drop in the maximal force production, and an increase in enslaving. We conclude that studies of synergies reveal two aspects of synergic control differentially affected by cortical stroke.
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Exposure to blast overpressure (BOP) is associated with behavioral, cognitive, and neuroimaging abnormalities. We investigated the dynamic responses of cortical vasculature and its relation to microglia/macrophage activation in mice using intravital two-photon microscopy following mild blast exposure. We found that blast caused vascular dysfunction evidenced by microdomains of aberrant vascular permeability. ⋯ Repetitive, but not single, BOPs also caused TNFα elevation two weeks post-blast. In addition, following a single BOP we found that aberrantly phosphorylated tau rapidly accumulated in perivascular domains, but cleared within four hours, suggesting it was removed from the perivascular area, degraded, and/or dephosphorylated. Taken together these findings argue that mild blast exposure causes an evolving CNS insult that is initiated by discrete disturbances of vascular function, thereby setting the stage for more protracted and more widespread neuroinflammatory responses.
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Excitatory amino acid carrier 1 (EAAC1) is one important subtype of the excitatory amino acid transporters (EAATs), and its absence can increase the vulnerability to oxidative stress in neural tissue. Enhanced expression of EAAC1 can provide neuroprotection in multiple disorders, including ischemia and multiple sclerosis. However, the mechanism regulating EAAC1 expression is not fully understood. ⋯ Overall, our work characterizes a signaling pathway by which E2 transactivates FGFR-ERK to induce EAAC1 expression in an FGF2-dependent manner. This occurs through SphK1 activation via GPR30 and leads to a resistance to H2O2 toxicity. This signal transduction pathway may provide novel insights into our understanding of the neuroprotective effects of E2 and may reveal new therapeutic targets or drugs for regulating the oxidative toxicity effects of various neurological diseases.
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The most promising therapeutic approach to finding the cure for devastating demyelinating conditions is the identification of clinically safe pharmacological agents that can promote differentiation of endogenous oligodendrocyte precursor cells (OPCs). Here we show that the breast cancer medication tamoxifen (TMX), with well-documented clinical safety and confirmed beneficial effects in various models of demyelinating conditions, stimulates differentiation of rat glial progenitors to mature oligodendrocytes in vitro. Clinically applicable doses of TMX significantly increased both the number of CNPase-positive oligodendrocytes and protein levels of myelin basic protein, measured with Western blots. ⋯ In contrast to TMXC and 4-hydroxy-TMX, endoxifen also induced astrogliogenesis, but independent of the ER activation. In sum, we showed that the TMX prodrug and its two main metabolites (4-hydroxy-TMX and endoxifen) promote ER-dependent oligodendrogenesis in vitro, not reported before. Given that differentiating effects of TMX were achieved with clinically safe doses, TMX is likely one of the most promising FDA-approved drugs for the possible treatment of demyelinating diseases.