Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.
  • Corrigendum

    21 February 2019

  • Myelin oligodendrocyte glycoprotein antibodies in neurological disease.

    19 February 2019

    Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies (MOG-Abs) were first detected by immunoblot and enzyme-linked immunosorbent assay nearly 30 years ago, but their association with multiple sclerosis (MS) was not specific. Use of cell-based assays with native MOG as the substrate enabled identification of a group of MOG-Ab-positive patients with demyelinating phenotypes. Initially, MOG-Abs were reported in children with acute disseminated encephalomyelitis (ADEM). Further studies identified MOG-Abs in adults and children with ADEM, seizures, encephalitis, anti-aquaporin-4-antibody (AQP4-Ab)-seronegative neuromyelitis optica spectrum disorder (NMOSD) and related syndromes (optic neuritis, myelitis and brainstem encephalitis), but rarely in MS. This shift in our understanding of the diagnostic assays has re-invigorated the examination of MOG-Abs and their role in autoimmune and demyelinating disorders of the CNS. The clinical phenotypes, disease courses and responses to treatment that are associated with MOG-Abs are currently being defined. MOG-Ab-associated disease is different to AQP4-Ab-positive NMOSD and MS. This Review provides an overview of the current knowledge of MOG, the metrics of MOG-Ab assays and the clinical associations identified. We collate the data on antibody pathogenicity and the mechanisms that are thought to underlie this. We also highlight differences between MOG-Ab-associated disease, NMOSD and MS, and describe our current understanding on how best to treat MOG-Ab-associated disease.

  • Time-Dependent, HIV-Tat-Induced Perturbation of Human Neurons In Vitro: Towards a Model for the Molecular Pathology of HIV-Associated Neurocognitive Disorders.

    5 November 2018

    A significant proportion of human immunodeficiency virus type 1 (HIV)-positive individuals are affected by the cognitive, motor and behavioral dysfunction that characterizes HIV-associated neurocognitive disorders (HAND). While the molecular etiology of HAND remains largely uncharacterized, HIV transactivator of transcription (HIV-Tat) is thought to be an important etiological cause. Here we have used mass spectrometry (MS)-based discovery proteomics to identify the quantitative, cell-wide changes that occur when non-transformed, differentiated human neurons are treated with HIV-Tat over time. We identified over 4000 protein groups (false discovery rate <0.01) in this system with 131, 118 and 45 protein groups differentially expressed at 6, 24 and 48 h post treatment, respectively. Alterations in the expression of proteins involved in gene expression and cytoskeletal maintenance were particularly evident. In tandem with proteomic evidence of cytoskeletal dysregulation we observed HIV-Tat induced functional alterations, including a reduction of neuronal intrinsic excitability as assessed by patch-clamp electrophysiology. Our findings may be relevant for understanding in vivo molecular mechanisms in HAND.

  • Ion dynamics during seizures.

    5 November 2018

    Changes in membrane voltage brought about by ion fluxes through voltage and transmitter-gated channels represent the basis of neural activity. As such, electrochemical gradients across the membrane determine the direction and driving force for the flow of ions and are therefore crucial in setting the properties of synaptic transmission and signal propagation. Ion concentration gradients are established by a variety of mechanisms, including specialized transporter proteins. However, transmembrane gradients can be affected by ionic fluxes through channels during periods of elevated neural activity, which in turn are predicted to influence the properties of on-going synaptic transmission. Such activity-induced changes to ion concentration gradients are a feature of both physiological and pathological neural processes. An epileptic seizure is an example of severely perturbed neural activity, which is accompanied by pronounced changes in intracellular and extracellular ion concentrations. Appreciating the factors that contribute to these ion dynamics is critical if we are to understand how a seizure event evolves and is sustained and terminated by neural tissue. Indeed, this issue is of significant clinical importance as status epilepticus-a type of seizure that does not stop of its own accord-is a life-threatening medical emergency. In this review we explore how the transmembrane concentration gradient of the six major ions (K(+), Na(+), Cl(-), Ca(2+), H(+)and [Formula: see text]) is altered during an epileptic seizure. We will first examine each ion individually, before describing how multiple interacting mechanisms between ions might contribute to concentration changes and whether these act to prolong or terminate epileptic activity. In doing so, we will consider how the availability of experimental techniques has both advanced and restricted our ability to study these phenomena.

  • Treatment of infants with epilepsy: Common practices around the world.

    5 November 2018

    OBJECTIVES: High quality data to guide recommendations for infants with epilepsy are lacking. This study aimed to develop an understanding of common practice and regional variations in the treatment interventions of infants with epilepsy, and also to identify areas for further study and to highlight where common practice occurs without sound evidence. METHOD: A survey addressed clinical treatment practice for infants with epilepsy. Alternative interventions were included. RESULTS: The survey found that most regions had similar practice for first-line interventions, except for North America, where more levetiracetam was prescribed. There was a preference for valproate as first-line therapy for generalized seizures, myoclonic seizures, and Dravet syndrome; only Oceania differed for generalized and myoclonic seizures. Phenobarbital was used for generalized and focal seizures in resource-poor and resource-equipped regions. Carbamazepine and oxcarbazepine were the preferred agents for focal seizures from all regions except North America, which uses more levetiracetam. For second- and third-line interventions, the range of choices was diverse, often with little correlation across regions. The ketogenic diet, vagus nerve stimulation, and epilepsy surgery were considered viable choices in most settings, but usually only once seizures were considered medically refractory. The survey highlighted the marked discrepancy in Africa, the one region that consistently confirmed a lack of access to these alternative interventions and to the newer antiepileptic drugs. SIGNIFICANCE: More randomized controlled trials in infants with seizures are needed to permit useful recommendations. The survey identified widespread use of levetiracetam in North America, which may be the result of effective marketing or based on good clinical practice. The widespread use of valproate may have safety implications. The lack of access to care in the African region highlighted the need for more sustained resources. Although the survey was not evidence based, the findings could be useful to support additional well-designed studies.

  • Biophysical models reveal the relative importance of transporter proteins and impermeant anions in chloride homeostasis.

    5 November 2018

    Fast synaptic inhibition in the nervous system depends on the transmembrane flux of Cl- ions based on the neuronal Cl- driving force. Established theories regarding the determinants of Cl- driving force have recently been questioned. Here, we present biophysical models of Cl- homeostasis using the pump-leak model. Using numerical and novel analytic solutions, we demonstrate that the Na+/K+-ATPase, ion conductances, impermeant anions, electrodiffusion, water fluxes and cation-chloride cotransporters (CCCs) play roles in setting the Cl- driving force. Our models, together with experimental validation, show that while impermeant anions can contribute to setting [Cl-]i in neurons, they have a negligible effect on the driving force for Cl- locally and cell-wide. In contrast, we demonstrate that CCCs are well-suited for modulating Cl- driving force and hence inhibitory signaling in neurons. Our findings reconcile recent experimental findings and provide a framework for understanding the interplay of different chloride regulatory processes in neurons.

  • Openspritzer: an open hardware pressure ejection system for reliably delivering picolitre volumes.

    5 November 2018

    The ability to reliably and precisely deliver picolitre volumes is an important component of biological research. Here we describe a high-performance, low-cost, open hardware pressure ejection system (Openspritzer), which can be constructed from off the shelf components. When connected to a standard micro-pipette via suitable pneumatic tubing, the device is capable of delivering minute doses of reagents to a wide range of biological and chemical systems. In this work, we characterise the performance of the device and compare it to a popular commercial system using two-photon fluorescence microscopy. We found that Openspritzer provides the same level of control over delivered reagent dose as the commercial system. Next, we demonstrate the utility of Openspritzer in a series of standard neurobiological applications. First, we used Openspritzer to deliver precise amounts of the neurotransmitters glutamate and GABA to hippocampal neurons to elicit time- and dose-precise excitatory and inhibitory responses, respectively. Second, we used Openspritzer to deliver infectious viral and bacterial agents to living tissue. Viral transfection of hippocampal interneurons with channelrhodopsin allowed for the optogenetic manipulation of hippocampal circuitry with light. Finally, we successfully used Openspritzer to infect organotypic hippocampal slice cultures with fluorescent Mycobacterium bovis bacilli. We anticipate that due to its high performance and low cost Openspritzer will be of interest to a broad range of researchers working in the life and physical sciences.