Neuroscience
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Our lab recently showed that N-methyl-D-aspartate (NMDA) evokes ATP-sensitive K(+) (K-ATP) currents in subthalamic nucleus (STN) neurons in slices of the rat brain. Both K-ATP channels and 5'-adenosine monophosphate-activated protein kinase (AMPK) are considered cellular energy sensors because their activities are influenced by the phosphorylation state of adenosine nucleotides. Moreover, AMPK has been shown to regulate K-ATP function in a variety of tissues including pancreas, cardiac myocytes, and hypothalamus. ⋯ In the presence of NMDA, A769662 inhibited depolarizing plateau potentials and burst firing, both of which could be antagonized by tolbutamide or dorsomorphin. These studies show that AMPK augments NMDA-induced K-ATP currents by a Ca(2+)-dependent process that involves nitric oxide and cGMP. By augmenting K-ATP currents, AMPK activation would be expected to dampen the excitatory effect of glutamate-mediated transmission in the STN.
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The partial opioid agonist thienorphine is currently in Phase II clinical trials in China as a candidate drug for the treatment of opioid dependence. However, its effect on synaptic plasticity in the NAc (nucleus accumbens) remains unclear. In the present study, we measured structural parameters of the synaptic interface to investigate the effect of thienorphine, morphine or a combination of both on synaptic morphology in the NAc of rats. ⋯ Furthermore, synaptophysin expression in the NAc was significantly greater after chronic administration of thienorphine, morphine, or both, than after saline. These results identified interesting differences between thienorphine and morphine in their effects on synaptic structure and synaptophysin expression in the rat NAc. Further study is deserved to investigate thienorphine as a new treatment for opioid dependence.
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Local peripheral injury activates satellite glial cells (SGCs) in sensory ganglia, which may contribute to chronic pain. We hypothesized that systemic inflammation affects sensory ganglia like local injury. We induced systemic inflammation in mice by injecting lipopolysaccharide (LPS) intraperitoneally, and characterized SGCs and neurons in dorsal root ganglia (DRG), using dye injection, calcium imaging, electron microscopy (EM), immunohistochemistry, and electrical recordings. ⋯ Sensitivity of SGCs to ATP increased twofold, and neuronal excitability was augmented. Blocking gap junctions reduced pain behavior in LPS-treated mice. Thus, changes in DRG due to systemic inflammation are similar to those due to local injury, which may explain the pain in sickness behavior and in other systemic diseases.
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Lower motor neuron dysfunction is one of the most debilitating neurological conditions and, as such, significantly impacts on the quality of life of affected individuals. Within the last decade, the engineering of mouse models of lower motor neuron diseases has facilitated the development of new therapeutic scenarios aimed at delaying or reversing the progression of these conditions. In this context, motor end plates (MEPs) are highly specialized regions on the skeletal musculature that offer minimally invasive access to the pre-synaptic nerve terminals, henceforth to the spinal cord motor neurons. ⋯ Targeting the entire MEP regions with FG increased the somatic availability of the retrograde tracer and, consequently, gave rise to FG-positive motor neurons that are organized into rostro-caudal columns spanning more spinal cord segments than previously reported. The results of this investigation will have positive implications for future studies involving the somatic delivery and retrograde transport of therapeutic transgenes into affected motor neurons. These data will also provide a framework for transgenic technologies aiming at maintaining the integrity of the neuromuscular junction for the treatment of lower motor neuron dysfunctions.