Neuroscience
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Myasthenia gravis (MG) is a relatively rare neurological disease that is usually associated with antibodies to the acetylcholine receptor (AChR). These antibodies (Abs) cause loss of the AChRs from the neuromuscular junction (NMJ), resulting in muscle weakness that can be life-threatening. Another form of the disease is caused by antibodies to muscle specific kinase (MuSK) that result in impaired AChR clustering and numbers at the NMJ, and may also interfere with presynaptic adaptive mechanisms. ⋯ All four conditions can be diagnosed by specific clinical features, electromyography and serum antibody tests, and can be treated effectively by a combination of pharmacological approaches and procedures that reduce the levels of the IgG antibodies. They form the first of a spectrum of diseases in which serum autoantibodies bind to extracellular domains of neuronal proteins throughout the nervous system and lead to constellations of clinical features including paralysis, sensory disturbance and pain, memory loss, seizures, psychiatric disturbance and movement disorders. This review will briefly summarize the ways in which this field has developed, since the 1970s when considerable contributions were made in Ricardo Miledi's laboratory at UCL.
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Gambierol is a marine polycyclic ether toxin, first isolated from cultured Gambierdiscus toxicus dinoflagellates collected in French Polynesia. The chemical synthesis of gambierol permitted the analyses of its mode of action which includes the selective inhibition of voltage-gated K+ (KV) channels. In the present study we investigated the action of synthetic gambierol at vertebrate neuromuscular junctions using conventional techniques. ⋯ Results show that nanomolar concentrations of gambierol inhibited the fast K+ current and prolonged the duration of the presynaptic action potential in motor nerve terminals, as revealed by presynaptic focal current recordings, increased stimulus-evoked quantal content in junctions blocked by high Mg2+-low Ca2+ medium, and by BoNT/A, reversed the postsynaptic block produced by d-tubocurarine and increased the transient Ca2+ signals in response to nerve-stimulation (1-10 Hz) in nerve terminals loaded with fluo-3/AM. The results suggest that gambierol, which on equimolar basis is more potent than 3,4-diaminopyridine, can have potential application in pathologies in which it is necessary to antagonize pre- or post-synaptic neuromuscular block, or both. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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Erythropoietin (EPO) is a hematopoietic growth factor that has an important role in the erythropoiesis. EPO and its receptor (EPO-R) are expressed all over in the mammalian brain. Furthermore, it has been reported that EPO may exert neuroprotective effect in animal models of brain disorders as ischemia and epilepsy. ⋯ Our findings show a new modulatory action of EPO on GABAA receptors (GABAA-Rs). This effect could be relevant to balance the GABAergic dysfunction in human TLE. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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The striatal cholinergic system is key in detecting changes in instrumental contingencies. While recent evidence supports this vision, cell type-specific online control on the activity of the cholinergic striatal neurons is necessary to empirically test it. ⋯ Remarkably, a manipulation that perturbs the activity of CINs, rather than inhibiting them also impaired the encoding of the change in contingency. These results emphasize that beyond an increase in the activity of CINs, the intact activity of these cells is required for the identification of an instrumental contingency change.
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Randomized Controlled Trial
Early exercise after intracerebral hemorrhage inhibits inflammation and promotes neuroprotection in the sensorimotor cortex in rats.
The present study examined the effect of early exercise on brain damage and recovery of motor function following intracerebral hemorrhage (ICH) in rats. Subjects were randomly assigned to no training after ICH (ICH), no training after sham surgery (SHAM), early treadmill exercise after ICH (ICH + ET), and late treadmill exercise after ICH (ICH + LT) groups. The ICH + ET and ICH + LT groups were trained for seven consecutive days starting on day 2 and day 9 after surgery, respectively. ⋯ Expression of IL-1b mRNA was significantly lower in the ICH + ET group than that in the ICH group. Collectively, these results suggest that early treadmill exercise after ICH promotes recovery of sensorimotor function by preventing neuronal death and ensuing cortical atrophy and by preserving dendritic structure compared with late treadmill exercise and no exercise. Early exercise may prevent neurodegeneration and functional loss by inhibiting neuroinflammation.