Neuroscience
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Serotonin is an important neurotransmitter and neuromodulator. Disruption of the serotonergic system has been implicated in various psychiatric disorders such as schizophrenia and bipolar disorder. Most of the drugs targeting these neurotransmitter systems are classified primarily as agonists or inverse agonists/antagonists, with their described function being limited to activating the canonical signaling pathway(s), or inhibiting the pathway(s) respectively. ⋯ Using site-specific mutagenesis we have identified residues important for this functional selectivity, shown by dopamine at this receptor. Our identification of specific residues important in the functional selectivity of dopamine at 5-HT2A could have far reaching implications for the field of GPCR signaling and drug-design. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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A new mammalian neuromuscular preparation is introduced for physiology and microscopy of all sorts: the intrinsic muscle of the mouse ear. The great utility of this preparation is demonstrated by illustrating how it has permitted us to develop a wholly new technique for staining muscle T-tubules, the critical conductive-elements in muscle. This involves sequential immersion in dilute solutions of osmium and ferrocyanide, then tannic acid, and then uranyl acetate, all of which totally blackens the T-tubules but leaves the muscle pale, thereby revealing that the T-tubules in mouse ear-muscles become severely distorted in several pathological conditions. ⋯ These new observations strongly encourage further in-depth studies of ear-muscle architecture, in the many available mouse-models of various devastating human muscle-diseases. Finally, we demonstrate that the delicate and defined physical characteristics of this 'new' mammalian muscle are ideal for ultrastructural study, and thereby facilitate the imaging of synaptic vesicle membrane recycling in mammalian neuromuscular junctions, a topic that is critical to myasthenia gravis and related diseases, but which has, until now, completely eluded electron microscopic analysis. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.
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The cerebellum harbors a specialized area on the roof of the fourth ventricle that is composed of glial cells and neurons that interface with the cerebrospinal fluid. This region includes the so-called ventromedial cord (VMC), which is composed of cells that are glial fibrillary acidic protein (GFAP)-positive and nestin-positive and distributes along the midline in association with blood vessels. We hypothesized that these cells should compare to GFAP and nestin-positive cells that are known to exist in other areas of the brain, which undergo proliferation and differentiation under hypoxic conditions. ⋯ This EGFP loss was supported by western blot analysis, which also showed a loss in the astrocyte-markers GFAP and ALDH1L1. On the other hand, other cell-markers appeared to be upregulated in the blots (including nestin, NeuN, and Iba1). Finally, we found that HPC does not remarkably affect the incorporation of BrdU into cells on the cerebellum, but strongly augments BrdU incorporation into periventricular cells on the floor of the fourth ventricle over the adjacent medulla.
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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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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.