Neuroscience
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Review
Ubiquitination and E3 Ubiquitin Ligases in Rare Neurological Diseases with Comorbid Epilepsy.
Ubiquitination is a post-translational modification that can dynamically alter the function, degradation and transport of a protein, as well as its interaction with other proteins, and activity of an enzyme. Dysfunctional ubiquitination is detrimental to normal cellular functions, and can result in severe diseases. Over the last decade, although much research has focused on deciphering the role of the ubiquitination/ubiquitin proteasome system (UPS) in the onset and progression of various neurological disorders, the specific relationship between ubiquitination and various epilepsies has not been carefully reviewed. ⋯ Here, we review the role of ubiquitination in maintaining normal cellular activities in neurons and recent findings on the dysregulation of ubiquitination in epilepsy. We particularly focus on rare neurological disorders with comorbid epilepsy in the hope of drawing more attention to this area. Through categorizing epilepsy-associated E3 ubiquitin ligases and their substrates and discussing ubiquitination-related rare neurological disorders, we summarize where the field stands at the moment and what directions we should consider in the future.
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The triceps surae is comprised of the soleus, and medial (MG) and lateral (LG) gastrocnemii. Modulation of triceps surae motor units (MUs) is context- and muscle-dependent, yet it is unknown how the disparate components of the triceps surae work together to achieve the common goal of high-intensity voluntary isometric plantar flexion torque gradation. Thus, the purpose was to assess the interrelationships between MU recruitment thresholds (MURTs) and MU discharge rates (MUDRs) among these three muscles during contractions from low to high intensities. ⋯ Initial MUDRs were 35% and 26% greater for the LG compared with the MG (p < 0.0001) and soleus (p < 0.0001), but no difference was detected between the MG and soleus (p = 0.28). Finally, initial MUDRs displayed a positive relationship with MURTs for each independent triceps surae component (p ≤ 0.002). The relative differences in MU properties of each muscle in this synergistic group illustrate that MU control strategies are likely optimized with respect to the relative contribution of each muscle to plantar flexion torque or functional roles.
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Posttraumatic epilepsy (PTE) is a long-term negative consequence of traumatic brain injury (TBI) in which recurrent spontaneous seizures occur after the initial head injury. PTE develops over an undefined period during which circuitry reorganization in the brain causes permanent hyperexcitability. The pathophysiology by which trauma leads to spontaneous seizures is unknown and clinically relevant models of PTE are key to understanding the molecular and cellular mechanisms underlying the development of PTE. ⋯ We found a significant increase in AQP4 in the ipsilateral frontal cortex and hippocampus of mice that developed PTE compared to those that did not develop PTE. Interestingly, AQP4 was found to be mislocalized away from the perivascular endfeet and towards the neuropil in mice that developed PTE. Here, we report for the first time, AQP4 dysregulation in a model of PTE which may carry significant implications for epileptogenesis after TBI.
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Whole-body movements are performed daily, and humans must constantly take into account the inherent instability of a standing posture. At times these movements may be performed in risky environments and when facing different costs of failure. The aim of the study was to test the hypothesis that in upright stance participants continuously estimate both probability of failure and cost of failure such that their postural responses will be based on these estimates. ⋯ Results showed also that the participants' estimates of the probability of failure accounted for their own inherent instability. Moreover, participants showed a tendency to overweight large probabilities of failure with more biomechanically constrained standing postures that results in suboptimal estimates of risky environments. Overall, our results suggest that participants tune their standing postural responses by empirically estimating the cost of failure and the uncertainty level in order to minimize the risk of falling when cost is high.
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Major depressive disorders (MDD) and chronic pain (CP) affect significant portion of the world's population and have high comorbidity rate. Social defeat stress (SDS) model was standardized in mice and can trigger depressive-like behavior and chronic pain. Based especially on clinical trials showing an effective preventive and therapeutic effect of physical exercise on CP and symptoms associated with MDD, this study aimed to investigate if the voluntary running wheel exercise can exert these effects in mice submitted to the 10-day SDS protocol, using fluoxetine as positive control. ⋯ Our results showed that the voluntary running wheel exercise was more effective than fluoxetine reversing the SDS-induced persistent hyperalgesia and both, fluoxetine and voluntary running wheel exercise, was effective reversing SDS-induced social avoidance. Also, voluntary running wheel exercise is an effective tool preventing both hyperalgesia and social avoidance induced by SDS. To the best of our knowledge, this was the first study using physical exercise as a therapeutic and preventive tool for chronic pain and depressive-like behavior simultaneously induced by social stress.