Neuroscience
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Huntington's disease (HD) is an autosomal dominant tandem repeat expansion disorder involving cognitive, psychiatric and motor symptoms. The expanded trinucleotide (CAG) repeat leads to an extended polyglutamine tract in the huntingtin protein and a subsequent cascade of molecular and cellular pathogenesis. One of the key features of neuropathology, which has been shown to precede the eventual loss of neurons in the cerebral cortex, striatum and other areas, are changes to synapses, including the dendritic protrusions known as spines. ⋯ In mouse models, synaptic and cortical plasticity deficits have been directly correlated with the onset of cognitive deficits, implying a causal link. Furthermore, following the discovery that environmental enrichment can delay onset of affective, cognitive and motor deficits in HD transgenic mice, specific synaptic molecules shown to be dysregulated by the polyglutamine-induced toxicity were also found to be beneficially modulated by environmental stimulation. This identifies potential molecular targets for future therapeutic developments to treat this devastating disease.
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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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To investigate the role of glutamate receptor subtypes and GABA in orofacial function, six individual topographies of orofacial movement, both spontaneous and induced by the dopamine D1-like receptor agonist [R/S]-3-methyl-6-chloro-7,8-dihydroxy-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF 83959), were quantified in mutant mice with deletion of (a) GluN2A, B or D receptors, and (b) the GABA synthesizing enzyme, 65-kD isoform of glutamate decarboxylase (GAD65). In GluN2A mutants, habituation of head movements was disrupted and vibrissae movements were reduced, with an overall increase in locomotion; responsivity to SKF 83959 was unaltered. In GluN2B mutants, vertical and horizontal jaw movements and incisor chattering were increased, with an overall decrease in locomotion; under challenge with SKF 83959, head and vibrissae movements were reduced. ⋯ In GAD65 mutants, vertical jaw movements were increased, with disruption to habituation of locomotion; under challenge with SKF 83959, vertical and horizontal jaw movements and incisor chattering were decreased. Effects on orofacial movements differed from their effects on regulation of overall locomotor behavior. These findings (a) indicate novel, differential roles for GluN2A, B and D receptors and for GAD65-mediated GABA in the regulation of individual topographies of orofacial movement and (b) reveal how these roles differ from and/or interact with the established role of D1-like receptors in pattern generators and effectors for such movements.
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The cytoarchitecturally-homogeneous appearance of the globus pallidus, subthalamic nucleus and substantia nigra has long been said to imply a high degree of afferent convergence and sharing of inputs by nearby neurons. Moreover, axon collaterals of neurons in the external segment of the globus pallidus and the substantia nigra pars reticulata arborize locally and make inhibitory synapses on other cells of the same type. These features suggest that the connectivity of the basal ganglia may impose spike-time correlations among the cells, and it has been puzzling that experimental studies have failed to demonstrate such correlations. ⋯ The patterns of spike-timing among such neurons depend on the ionic mechanism of pacemaking, the level of background uncorrelated cellular and synaptic noise, and the firing rates of the neurons, as well as the properties of their synaptic connections. Application of these concepts to the basal ganglia circuitry suggests that the connectivity and physiology of these nuclei may be configured to prevent the establishment of permanent spike-timing relationships between neurons. The development of highly synchronous oscillatory patterns of activity in Parkinson's disease may result from the loss of pacemaking by some basal ganglia neurons, and accompanying breakdown of the mechanisms responsible for active decorrelation.
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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.