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Mice injected spinally with rAAV-C1q-c-shRNA-GFP showed an increase in spine density on spinal neurons as compared to rAAV-scrambled-shRNA-GFP-injected mice ( Figures 8C and 8F). In contrast, following intrathecal application of recombinant C1q in inflamed mice, CFA-associated increase in spine density was significantly reduced ( Figures 8C and 8D). Similarly, following stereotaxic Tyrosine Kinase Inhibitor Library in?vivo injection of C1q in the hippocampus of adult mice, a significant reduction in spine density of pyramidal neurons of CA1 region was observed ( Figure?8E). Finally, nuclear calcium-evoked spinal C1q downregulation was simulated by injection of rAAV-C1q-c-shRNA-GFP (using rAAV-scrambled-RNA as a control) into the spinal dorsal horn. Whereas basal mechanical sensitivity was largely unaltered upon spinal C1q knockdown, the extent of inflammatory mechanical hypersensitivity in these mice was significantly increased when compared to mice expressing scrambled control RNA ( Figures 8G, S7A, and S7B). Conversely, when we intrathecally applied recombinant trimeric C1q, significant attenuation of CFA-induced mechanical and thermal hypersensitivity was observed ( Figures 8H, 8I, S7C, and S7D; p?Lonafarnib cost provide evidence for a nuclear calcium target gene in the modulation of?inflammation-associated pain hypersensitivity as well as structural plasticity. The interplay among synaptic receptors, cytoplasmic effectors, and the nucleus plays a critical role in linking membrane depolarization to gene transcription. Here, we show that high-threshold, persistent nociceptive input leads to calcium entry into the nuclei?of spinal dorsal VAV2 horn neurons, which exhibit a specific transcriptional response, and that this stimulation drives structural remodelling in spinal excitatory neurons and functional changes leading to chronic inflammatory hypersensitivity. We observed that progressively augmenting recruitment of A-delta afferents and C-type nociceptors as well as stimulating nociceptors with increasing frequencies led to progressively larger amplitude activity evoked nuclear calcium signals, suggesting that nuclear calcium integrates spinal neuron input from persistent activation of nociceptors after injury. Interestingly, using constant stimulation parameters in naive or CFA-inflamed mice, we found no detectable differences in the characteristics of evoked nuclear calcium signals, consistent with the concept that nuclear calcium transients are upstream, not downstream, of activity-induced plasticity.