Neuroscience
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To be highly reliable, synaptic transmission needs postsynaptic receptors (Rs) in precise apposition to the presynaptic release sites. At inhibitory synapses, the postsynaptic protein gephyrin self-assembles to form a scaffold that anchors glycine and GABAARs to the cytoskeleton, thus ensuring the accurate accumulation of postsynaptic receptors at the right place. This protein undergoes several post-translational modifications which control protein-protein interaction and downstream signaling pathways. ⋯ In addition, we will focus on the impact of gephyrin structure and distribution at the nanoscale level on the functional properties of inhibitory synapses as well as the implications of this scaffold protein in synaptic plasticity processes. Finally, we will emphasize how gephyrin genetic mutations or alterations in protein expression levels are implicated in several neuropathological disorders, including autism spectrum disorders, schizophrenia, temporal lobe epilepsy and Alzheimer's disease, all associated with severe deficits of GABAergic signaling. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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In the CNS, chemokines and chemokine receptors are involved in pleiotropic physiological and pathological activities. Several evidences demonstrated that chemokine signaling in the CNS plays key homeostatic roles and, being expressed on neurons, glia and endothelial cells, chemokines mediate the bidirectional cross-talk among parenchymal cells. ⋯ In this review we summarize the evidence that chemokines (CXCL12, CX3CL1, CXCL16 and CCL2) modulate neuroprotective processes upon different noxious stimuli and participate to orchestrate neurons-microglia-astrocytes action to preserve and limit brain damage. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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Reactive oxygen species (ROS) are best known for being involved in cellular metabolism and oxidative stress, but also play important roles in cell communication. ROS signaling has become increasingly recognized as a mechanism implicated in the regulation of synaptic neurotransmission, under both physiological and pathological conditions. Hydrogen peroxide (H2O2) and superoxide anion are the main biologically relevant endogenous ROS in the nervous system. ⋯ ROS induce changes on both, the activity of phasic and tonic GABAA receptors and GABA release from presynaptic terminals. Based on these facts, ROS signaling is discussed as a possible selective mechanism linking cellular metabolism to inhibitory neurotransmission through the direct or indirect modulation of the GABAA receptor function. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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Post-translational modification of Tau, a microtubule-associated protein in the neuronal cell, plays a major role in Alzheimer's disease. Tau is an axonal protein expressed in mature neurons that promote the self-assembly of tubulin into microtubules and its stabilization in neurons. Phosphorylation of Tau makes it prone to aggregation at the intra-neuronal region leading to impaired neurotransmission and dementia. ⋯ Here we highlight the role of GPCRs in Tau phosphorylation and Tau interaction in different cells of the nervous system. Hence, the role of GPCRs are attaining more attention in the therapeutic field of Alzheimer's disease. Specific agonists/antagonists and allosteric modulators could be the potential target for therapy against GPCR-mediated Tau phosphorylation in Alzheimer's disease.
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Review
'Fragmentation' of NMJs: a sign of degeneration or regeneration? A long journey with many junctions.
Mammalian neuromuscular junctions (NMJs) often consist of curved bands of synaptic contact, about 3-6 μm wide, which resemble pretzels. This contrasts with the NMJs of most animal species which consist of a cluster of separate synaptic spots, each of which is also about 3-6 μm across. In a number of situations, including a variety of disease states as well as normal ageing, mammalian NMJs acquire a more 'fragmented' appearance that resembles somewhat that of other species. ⋯ Further, where appropriate studies have been performed, no evidence of a correlation between the degree of fragmentation and the efficacy of transmission has emerged. It may therefore be more appropriate to consider NMJ 'fragmentation' as a form of regeneration, rather than of degeneration. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.