Frontiers in molecular neuroscience
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Opioid activation of the mu opioid receptor (MOR) promotes signaling cascades that evoke both analgesic responses to pain and side effects like addiction and dependence. Manipulation of these cascades, such as by biased agonism, has great promise to improve opioid therapy. However, the signaling cascades of the MOR are in general poorly understood, providing few targets for drug development. ⋯ Lastly, we used cycloheximide treatment in the brain to demonstrate that rapid protein translation within 30 min of opioid treatment is required for Hsp90 regulation of opioid response. Together these studies provide insight into the molecular mechanisms by which Hsp90 promotes opioid anti-nociception. These findings thus both improve our basic science knowledge of MOR signal transduction and could provide future targets for clinical intervention to improve opioid therapy.
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γ-Aminobutyric acid type A receptors (GABAARs) mediate the majority of fast synaptic inhibition in the central nervous system (CNS). GABAARs belong to the Cys-loop superfamily of pentameric ligand-gated ion channels (pLGIC) and are assembled from 19 different subunits. As dysfunctional GABAergic neurotransmission manifests itself in neurodevelopmental disorders including epilepsy and anxiety, GABAARs are key drug targets. ⋯ This review article will highlight recent advances in understanding the structure of heteropentameric synaptic GABAARs and how these structures have provided fundamental insights into the assembly of these multi-subunit receptors as well as their modulation by diverse ligands including the physiological agonist GABA. We will further discuss the role of gephyrin in the anchoring of synaptic GABAARs and glycine receptors (GlyRs), which are crucial for maintaining the architecture of the iPSD. Finally, we will also summarize how anti-malarial artemisinin drugs modulate gephyrin-mediated inhibitory neurotransmission.
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Neuronal inhibition can be defined as a spatiotemporal restriction or suppression of local microcircuit activity. The importance of inhibition relies in its fundamental role in shaping signal processing in single neurons and neuronal circuits. In this context, the activity of inhibitory interneurons proved the key to endow networks with complex computational and dynamic properties. ⋯ This review elaborates current knowledge on cerebellar inhibitory interneurons [Golgi cells, Lugaro cells (LCs), basket cells (BCs) and stellate cells (SCs)], starting from their ontogenesis and moving up to their morphological, physiological and plastic properties, and integrates this knowledge with that on the more renown granule cells and PCs. We will focus on the circuit loops in which these interneurons are involved and on the way they generate feed-forward, feedback and lateral inhibition along with complex spatio-temporal response dynamics. In this perspective, inhibitory interneurons emerge as the real controllers of cerebellar functioning.
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Zika virus (ZIKV) is an emerging flavivirus rapidly spreading throughout the tropical Americas. Aedes mosquitoes is the principal way of transmission of the virus to humans. ZIKV can be spread by transplacental, perinatal, and body fluids. ⋯ ZIKV has been linked to a number of central and peripheral nervous system injuries such as Guillain-Barré syndrome (GBS), transverse myelitis (TM), meningoencephalitis, ophthalmological manifestations, and other neurological complications. Nevertheless, mechanisms of host-pathogen neuro-immune interactions remain incompletely elucidated. This review provides a critical discussion about the possible mechanisms underlying the development of autoimmune neurological conditions associated with Zika virus infection.
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Stroke is a neurological disease with high disability and fatality rates, and ischemic stroke accounts for 75% of all stroke cases. The underlying pathophysiologic processes of ischemic stroke include oxidative stress, toxicity of excitatory amino acids, excess calcium ions, increased apoptosis and inflammation. ⋯ Because of the potentially important role, lncRNAs might be useful as biomarkers for the diagnosis, treatment and prognosis of ischemic stroke. This article reviews the functions of lncRNAs in different pathophysiology events of ischemic stroke with a focus on specific lncRNAs that may underlie ischemic stroke pathophysiology and that could therefore serve as potential diagnostic biomarkers and therapeutic targets.