Neuroscience
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GPR81 is a G-protein coupled receptor (GPCR) discovered in 2001, but deorphanized only 7 years later, when its affinity for lactate as an endogenous ligand was demonstrated. More recently, GPR81 expression and distribution in the brain were also confirmed and the function of lactate as a volume transmitter has been suggested since then. These findings shed light on a new function of lactate acting as a signaling molecule in the central nervous system, in addition to its well-known role as a metabolic fuel for neurons. ⋯ The activation of GPR81 showed promising results for neuroprotection: it modulates many processes involved in the pathophysiology of ischemia. In this review, we summarize the history of GPR81, starting with its deorphanization; then, we discuss GPR81 expression and distribution, signaling transduction cascades, and neuroprotective roles. Lastly, we propose GPR81 as a potential target for the treatment of cerebral ischemia.
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Case Reports
Functional Evaluation of a Novel GRIN2B Missense Variant Associated with Epilepsy and Intellectual Disability.
Epilepsy, a neurological condition, is widely prevalent among individuals with intellectual disability (ID). It is well established that N-methyl-D-aspartate (NMDA) receptors play an important role in both epilepsy and ID. Autosomal dominant mutations in the GRIN2B gene, which encodes the GluN2B subunit of the NMDA receptor, have been reported to be associated with epilepsy and ID. ⋯ It is accompanied by reduced delivery of the receptors to the cell membrane and a decrease in glutamate affinity. Moreover, primary neurons expressing GluN2B-K1091T also exhibited impaired surface expression of NMDA receptors, a reduction in dendritic spine number and excitatory synaptic transmission. In summary, our study reports a novel GRIN2B mutation and provides functional characteristics of this mutation in vitro, thereby contributing to the understanding of GRIN2B variants in epilepsy and ID.
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Visually guided reaching is a common motor behavior that engages subcortical circuits to mediate rapid corrections. Although these neural mechanisms have evolved for interacting with the physical world, they are often studied in the context of reaching toward virtual targets on a screen. These targets often change position by disappearing from one place reappearing in another instantaneously. ⋯ In one condition, the objects moved very rapidly from one place to another. In the other condition, illuminated targets instantaneously switched position by being extinguished in one position and illuminating in another. Participants were consistently faster in correcting their reach trajectories when the object moved continuously.
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Microglia play an ambiguous role in injury or repair after ischemia-reperfusion, and the induced oxidative stress serves as an important signal, mediates direct toxicity to nerve cells, and eventually simulates complex physiological processes such as activation of microglia to repair the damaged area. Herein, we show that sprouty-related protein with an EVH1 domain 1 (SPRED1) may act as a regulatory node in this phenomenon. The ischemic brain of an ischemia-reperfusion rat model constructed by middle cerebral artery occlusion (MCAO) showed an increase in oxidative stress and downregulation of SPRED1 expression. ⋯ In the absence of H2O2 induction, SPRED overexpression alone did not mediate such an effect. These findings indicate that SPRED1 tends to maintain intracellular homeostasis of signals, but the oxidative stress derived from ischemia-reperfusion can easily degrade SPRED1 and consequently re-activate these restricted signals and alter the behavior of microglia. Thus, our study reveals a novel role of SPRED1 in microglia in response to cerebral ischemia-induced oxidative stress.
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Alzheimer's disease (AD) is the most common neurodegenerative disease, and currently, no effective treatment strategies exist for this condition. MicroRNAs (miRNAs) have emerged as promising therapeutic targets of AD. Previous studies have highlighted the significant role of miR-146a-5p in regulating adult hippocampal neurogenesis (AHN). ⋯ Interestingly, both miR-146a-5p antagomir and p-Stat3 inhibitor obviously rescued neurogenesis and pattern separation in APP/PS1 mice. Moreover, application of miR-146a-5p agomir reversed the protective effects of Klf4 upregulation. These findings open new avenues for protection against AD through the modulation of neurogenesis and cognitive decline via the miR-146a-5p/Klf4/p-Stat3 pathway.