Neuroscience
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The complement of mechanisms underlying tau pathology in neurodegenerative disorders has yet to be elucidated. Among these mechanisms, abnormal tau phosphorylation has received the most attention because neurofibrillary tangles present in Alzheimer's disease (AD) and related disorders known as tauopathies are composed of hyperphosphorylated forms of this microtubule-associated protein. More recently, we showed that calpain-mediated cleavage leading to the generation of the 17kDa tau₄₅₋₂₃₀ fragment is a conserved mechanism in these diseases. ⋯ Furthermore, functional abnormalities were detected in the transgenic mice using Morris Water Maze and fear conditioning tests. These results suggest that the accumulation of tau₄₅₋₂₃₀ is responsible, at least in part, for neuronal degeneration and some behavioral changes in AD and other tauopathies. Collectively, these data provide the first direct evidence of the toxic effects of a tau fragment biologically produced in the context of these diseases in vertebrate neurons that develop in situ.
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Three structurally similar odorants trigger distinct signaling pathways in a mouse olfactory neuron.
In the mammalian olfactory system, one olfactory sensory neuron (OSN) expresses a single olfactory receptor gene. By calcium imaging of individual OSNs in intact mouse olfactory turbinates, we observed that a subset of OSNs (Ho-OSNs) located in the most ventral olfactory receptor zone can mediate distinct signaling pathways when activated by structurally similar ligands. Calcium imaging showed that Ho-OSNs were highly sensitive to 2-heptanone, heptaldehyde and cis-4-heptenal. 2-heptanone-evoked intracellular calcium elevation was mediated by cAMP signaling while heptaldehyde triggered the diacylglycerol pathway. ⋯ The feature that an olfactory receptor mediates multiple signaling pathways was specific for Ho-OSNs and not established in another population of OSNs characterized. Our study suggests that distinct signaling pathways triggered by ligand-induced conformational changes of an olfactory receptor constitute a complex information process mechanism in olfactory transduction. This study has important implications beyond olfaction in that it provides insights of plasticity and complexity of G-protein-coupled receptor activation and signal transduction.
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Melatonin, a neurohormone secreted mainly by the pineal gland, has a variety of physiological functions and neuroprotective effects. Previous studies have shown that melatonin could stimulate the proliferation of neural stem/progenitor cells (NS/PCs). Recent studies reported that the activities of mitogen-activated protein kinase (MAPK) of neural stem cells (NSCs) changed in response to the proliferative effect of melatonin. ⋯ The present results showed that melatonin could induce NS/PCs to proliferate by increasing phosphorylation of ERK1/2 and c-Raf through melatonin receptor. These results provide further evidence for a role of melatonin in promoting neurogenesis, adding to the remarkably pleiotropic nature of this neurohormone. This intrinsic modulator deserves further investigation to better understand its physiological and therapeutic implication.
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The laggard (lag) mutant mouse, characterized by hypomyelination and cerebellar ataxia, is a spontaneously occurring mutant mouse caused by mutation in the Kif14 gene. In this mutant mouse, the laminated structures such as the cerebral and cerebellar cortices and the dentate gyrus are cytoarchitecturally abnormal. Macroscopically, the olfactory bulb of the lag mutant mouse is smaller in size and more transparent than the normal counterpart. ⋯ In the mutant, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in the subventricular zone of the lateral ventricle are increased in number, especially at perinatal age, suggesting that the decreased population of granule cells in the lag mutant mouse is caused by the increased apoptotic cell death. The olfactory input appears to be intact, as indicated by anterograde labeling of olfactory nerves with an injection of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) into the olfactory mucosa. In conclusion, the olfactory bulb of the lag mutant mouse is cytoarchitecturally affected, suggesting that the causal gene for lag mutation, i.e., Kif14, has multiple effects on the development of laminated structures in the central nervous system in addition to the myelin formation.
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GABA is the neurotransmitter of striatal projection neurons, however the contribution of the striatal GABAergic output to behavior is not well understood. We assessed motor function, spatial learning, social behavior, olfactory and object recognition preferences in mice lacking the GABA-synthesizing enzyme glutamic acid decarboxylase, Gad67, in neurons expressing the protein Gpr88, an orphan G-protein-coupled receptor primarily expressed in the striatum. ⋯ These findings provide original evidence that striatal Gad67 expression is involved in the modulation of learning and social behavior. Some of the behavioral abnormalities observed in Gad67-deficient mice are reminiscent of Autism-spectrum-disorder (ASD) deficits, suggesting that abnormal striatal GABAergic output may contribute to behavioral deficits in ASD.