Neuroscience
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Both myelinated and unmyelinated afferents are implicated in transmitting diabetic neuropathic pain. Although unmyelinated afferents are generally considered to play a significant role in diabetic neuropathic pain, pathological changes in diabetic neuropathy occur mostly in myelinated A-fibers. In the present study, we first examined the role of capsaicin-sensitive C-fibers in the development of allodynia induced by diabetic neuropathy. ⋯ Furthermore, these afferent fibers had a lower threshold for activation and augmented responses to mechanical stimuli. Thus, our study suggests that capsaicin-sensitive C-fiber afferents are not required in the development of allodynia in this rat model of diabetes. Our electrophysiological data provide substantial new evidence that the abnormal sensory input from Adelta- and Abeta-fiber afferents may play an important role in diabetic neuropathic pain.
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In transgenic mice carrying the G93A human mutation of Cu/Zn superoxide dismutase (SOD1), which provide a model of familial amyotrophic lateral sclerosis, we investigated, before the onset of symptoms, two parameters of the response of facial motoneurons to nerve transection, i.e. nitric oxide synthase induction and motoneuron loss. Axotomy elicited after 2 and 3 weeks high nitric oxide synthase expression in facial motoneurons of wild-type mice, whereas the induction was very weak or absent in transgenic mice. ⋯ Thus, SOD1 mutation interferes with the oxidative cascade elicited by axonal injury in cranial motoneurons. The results also indicate that the adverse gain of function of the mutant SOD1 enhances the vulnerability of motoneurons to peripheral stressful conditions.
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In the present study we localized glial cell line-derived neurotrophic factor (GDNF), and the high affinity receptor for GDNF (GFRalpha-1) in the rat retina. We also examined the effects of neurturin on the survival of axotomized retinal ganglion cells (RGCs) and compared neurturin-mediated RGC rescue to GDNF and brain-derived neurotrophic factor (BDNF) neuroprotection. We administered combined injections of neurturin with BDNF or GDNF in order to determine if these factors rescue RGCs by different mechanisms. ⋯ These results suggest that neurturin, GDNF, and BDNF act independently to rescue injured RGCs. Our results also suggest that RGCs and retinal Müller cells may be responsive to GDNF because they both express GFRalpha-1. The present findings have implications for the rescue of injured retinal ganglion cells, as well as other CNS neurons that are responsive to neurturin, GDNF, and BDNF, including midbrain dopaminergic neurons and motor neurons.
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Delta-catenin (or neural plakophilin-related arm-repeat protein/neurojungin) is primarily a brain specific member of the p120(ctn) subfamily of armadillo/beta-catenin proteins that play important roles in neuronal development. Our previous studies have shown that the ectopic expression of delta-catenin induces the formation of dendrite-like extensions and that the overexpression of delta-catenin promotes dendritic branching and increases spine density. Here we demonstrate that delta-catenin displays a dendritic distribution pattern in the adult mouse brain and is co-enriched with postsynaptic density-95 (PSD-95) in the detergent insoluble postsynaptic scaffolds. ⋯ In dissociated hippocampal neurons overexpressing delta-catenin, glutamate stimulation leads to a rapid redistribution of delta-catenin that can be attenuated by 6-cyano-7-nitroquinoxaline-2,3-dione and dizocilpine, selective inhibitors of ionotropic glutamate receptors. Upon glutamate receptor activation, delta-catenin becomes down-regulated and its association with NR2A and mGluR1alpha in cultured neurons is diminished. These findings support a possible functional connection between delta-catenin and the glutamatergic excitatory synaptic signaling pathway during neuronal development.
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Axonal injury to CNS neurons results in apoptotic cell death. The processes by which axotomy signals apoptosis are diverse, and may include deprivation of target-derived factors, induction of injury factors, bursts of reactive oxygen species (ROS), and other mechanisms. Our previous studies demonstrated that death of a dissociated retinal ganglion cell, an identified CNS neuron, is ROS-dependent. ⋯ Culture of retinal ganglion cell with the non-thiol-containing reducing agent tris(carboxyethyl)phosphine resulted in long-term survival equivalent to or better than with neurotrophic factors. Our data suggest that axotomy-associated neuronal death induced by acute dissociation may be partly dependent on ROS production, acting to shift the redox state and oxidize one or more key thiols. Understanding the mechanisms by which ROS signal neuronal death could result in strategies for increasing their long-term survival after axonal injury.