Neuroscience
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Progranulin (PGRN) is known to play a role in the pathogenesis of neurodegenerative diseases. Recently, it has been demonstrated that patients with the homozygous mutation in the GRN gene present with neuronal ceroid lipofuscinosis, and there is growing evidence that PGRN is related to lysosomal function. In the present study, we investigated the possible role of PGRN in the lysosomes of activated microglia in the cerebral cortex after traumatic brain injury (TBI). ⋯ S6K1 phosphorylation in KO mice was significantly lower than that in WT mice. In addition, the number of nissl-positive and fluoro-jade B-positive cells around the injury was significantly decreased and increased, respectively, in KO as compared with WT mice. These results suggest that PGRN localized in the lysosome is involved in the activation of mTORC1, and its deficiency leads to increased TFEB nuclear translocation with a resultant increase in lysosomal biogenesis in activated microglia and exacerbated neuronal damage in the cerebral cortex after TBI.
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Synaptic plasticity, specifically long-term potentiation and long-term depression, is thought to be the underlying cellular mechanism for learning and memory processes in the brain. About two decades ago a new concept was introduced, namely metaplasticity, which comprises changes that modify the properties of synaptic plasticity due to a priming or preconditioning event. ⋯ We consider here whether it is helpful to conceptualize these latter effects as "behavioral metaplasticity", and in which sense this view fits into the original concept of metaplasticity. By integrating the literature on environmental effects on plasticity, especially stress, plus developmental aspects as well as genetic and epigenetic modifications, we shape the framework in which the term "behavioral metaplasticity" should be considered and discuss research directions that can help to unravel the mechanisms involved in both synaptic and behavioral metaplasticity.
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Diabetes is associated with an increased risk for brain disorders, namely cognitive impairments associated with hippocampal dysfunction underlying diabetic encephalopathy. However, the impact of a prediabetic state on cognitive function is unknown. Therefore, we now investigated whether spatial learning and memory deficits and the underlying hippocampal dysfunction were already present in a prediabetic animal model. ⋯ HSu rats displayed a poorer performance in hippocampal-dependent short- and long-term spatial memory performance, assessed with the modified Y-maze and Morris water maze tasks, respectively; this was accompanied by a reduction of insulin receptor-β density with normal levels of insulin receptor substrate-1 pSer636/639, and decreased hippocampal glucocorticoid receptor levels without changes of the plasma corticosterone levels. Importantly, HSu animals exhibited increased hippocampal levels of AMPA and NMDA receptor subunits GluA1 and GLUN1, respectively, whereas the levels of protein markers related to nerve terminals (synaptophysin) and oxidative stress/inflammation (HNE, RAGE, TNF-α) remained unaltered. These findings indicate that 9 weeks of sucrose consumption resulted in a metabolic condition suggestive of a prediabetic state, which translated into short- and long-term spatial memory deficits accompanied by alterations in hippocampal glutamatergic neurotransmission and abnormal glucocorticoid signaling.
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It is widely known that prenatal stress (PS) exposure causes depression-like behaviour to offspring, as well as maladaptive responses including neurobiological and physiological changes. However, the underlying mechanism of PS induced juvenile-onset depression remains largely unravelled. The inadequacies of monoamine deficiency hypothesis, the emerging evidence of altered glutamate neurotransmission in mood disorders, as well as our previous studies inspired us to assess the potential role of glutamatergic system in the pathogenesis of juvenile depression. ⋯ We also detected that PS significantly altered the expression of glutamate receptor and glutamate transporters of these depressed rats. In brief, the changes of phosphorylated GluR1 subunit of AMPAR protein level in the hippocampus and frontal cortex, as well as markedly decreased EAAT2 mRNA expression in the hippocampus, striatum and frontal cortex and EAAT3 mRNA expression in the hippocampus of stressed rats were both observed. These results underpinned that glutamate receptors and glutamate transporters might be involved in the progress of depression-like behaviour in juvenile rat offspring induced by PS.