Neuroscience
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β-Amyloid (Aβ) accumulation has been proved to be responsible for the pathogenesis of Alzheimer's disease (AD). However, it is not yet clear what makes Aβ accumulate and become toxic in the AD brains. Our previous studies demonstrated that glycated Aβ (Aβ-AGE) could be formed, and it exacerbated the authentic Aβ-mediated neurotoxicity in vitro, but we did not show the role of Aβ-AGE in vivo and the underlying mechanism. ⋯ We also observed the overexpression of receptor for advanced glycation endproducts receptor for AGEs (RAGE) and the activation of downstream molecular (GSK3, NF-κB, p38) in RAGE-mediated pathways. On the other hand, simultaneous application of RAGE antibody or GSK3 inhibitor LiCl reversed the cognitive decline amplified by Aβ-AGE. Our data revealed that in vivo the Aβ-AGE is more toxic than Aβ, and Aβ-AGE could lead to the aggravation of AD-like pathology though the RAGE pathway, suggesting that Aβ-AGE and RAGE may be new therapeutic targets for AD.
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Progesterone is a known anticonvulsant, with its inhibitory effects generally attributed to its secondary metabolite, 5α,3α-tetrahydroprogesterone (THP), and THP's enhancement of GABAA receptor activity. Accumulating evidence, however, suggests that progesterone may have non-genomic actions independent of the GABAA receptor. In this study, we explored THP/GABAA-independent anticonvulsive actions of progesterone in a mouse model of hippocampal kindling and in mouse entorhinal slices in vitro. ⋯ Carbamazepine mimicked the effects of progesterone with finasteride pretreatments in decreasing cortical discharges and motor seizures, whereas midazolam produced effects similar to progesterone alone or THP in decreasing hippocampal ADs and motor seizures. In brain slices, progesterone at 1μM inhibited entorhinal epileptiform potentials in the presence of picrotoxin and finasteride. We suggest that progesterone may have THP/GABAA-dependent and independent anticonvulsive actions in the hippocampal-kindled mouse model.
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Glial cell line-derived neurotrophic factor (GDNF) supports and maintains the neuromuscular system during development and through adulthood by promoting neuroplasticity. The aim of this study was to determine if different modes of exercise can promote changes in GDNF expression and neuromuscular junction (NMJ) morphology in slow- and fast-twitch muscles. Rats were randomly assigned to a run training (run group), swim training (swim group), or sedentary control group. ⋯ GDNF content and total end plate area were positively correlated. End plate area decreased in EDL of the run group and increased in SOL of the swim group. The results indicate that GDNF expression and NMJ morphological changes are activity dependent and that different changes may be observed by varying the exercise intensity in slow- and fast-twitch fibers.
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Noradrenaline acting via β-adrenoceptors (β-ARs) in the CNS plays an important role in learning/memory and cognitive functions. β-ARs have been shown to be expressed in cortical pyramidal and subcortical principal cells. However, little is known about β-AR expression in different subtypes of GABAergic neurons. ⋯ SST-ir interneurons are more likely to express β2-AR compared with the other subtypes of interneurons. The present results are of significance for understanding the role of β-ARs in prefrontal cortical functions.
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Neonatal handling, an experimental model of early life experiences, is known to affect hypothalamic-pituitary-adrenal (HPA) axis function, thus increasing adaptability, coping with stress, cognitive abilities and in general brain plasticity-related processes. AMPA receptors (AMPARs) mediate fast synaptic transmission at excitatory glutamatergic synapses in the CNS and are crucial during neuronal development, synaptic plasticity and structural remodeling. AMPARs are composed of four types of subunits, designated as AMPA glutamate receptor subunits (GluA1, GluA2, GluA3 and GluA4), which combine to form tetramers. ⋯ Furthermore, we observed that neonatal handling induced in both sexes decreases of GluA2 mRNA in the dorsal hippocampus, as well as in the somatosensory and occipital cortex, of GluA3 mRNA in most hippocampal areas, amygdaloid complex and cortical regions studied, and of GluA4 mRNA in the ventral hippocampus. These results show that glutamatergic transmission is markedly affected by an early experience. The neonatal handling-induced alterations in AMPAR subunit composition are in line with the increased brain plasticity, the more effective HPA axis function, and in general the more adaptive behavioral phenotype known to characterize the handled animals.