Neuroscience
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Although Ca2+ influx through muscle nAChR-channels has been described over the past 40 years, its functions remain still poorly understood. In this review we suggest possible roles of Ca2+ entry at all stages of muscle development, summarizing the evidence present in literature. nAChRs are expressed in myoblasts prior to fusion, and can be activated in the absence of an ACh-releasing nerve terminal, with Ca2+ influx likely contributing to regulate cell fusion. Upon establishment of nerve-muscle contact, Ca2+ influx contributes to orchestrate the signaling required for the correct formation of the neuromuscular junction. ⋯ However, when genetic defects cause excessive channel activation, Ca2+ influx becomes toxic and causes endplate myopathy. Throughout the review, we highlight how Ricardo Miledi has contributed to construct this whole body of knowledge, from the initial description of Ca2+ permeability of endplate nAChR channels, to the rationale for the treatment of endplate excitotoxic damage under pathological conditions. This article is part of a Special Issue entitled: SI: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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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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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.
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Review
Presynaptic Black Box Opened by Pioneers at Biophysics Department in University College London.
The mechanism of chemical synaptic transmission was elucidated at the frog neuromuscular junction (NMJ) and at the squid giant synapse by Katz, Miledi and other researchers. Later progress in molecular biology revealed numerous types of proteins in mammalian central synapses. To establish molecular-functional correlation in synaptic transmission, it now seems essential to re-address the fundamental mechanisms at mammalian central synapses. ⋯ However, at the calyx of Held, unlike at the squid synapse, the input-output relationship had a wide safety margin, protecting transmitter release from a diminishment of presynaptic action potentials. As in the NMJ, Ca2+ remaining in the cytosol after action potential facilitates subsequent release. As a downstream mechanism of this residual Ca2+, a Ca2+-induced Ca2+ channel activation via high-affinity Ca2+ binding proteins was discovered at mammalian central synapses.