The IBRO Alumni Committee under the leadership of its Chair, Valeria della Maggiore (Universidad de Buenos Aires, Argentina), will hold an IBRO Alumni Symposium at the next Society for Neuroscience (SfN) Annual Meeting in San Diego, USA, on 14 November 2016. Five IBRO alumni from five different countries - Kinga Bercsenyi (UK), Thiago Cunha (Brazil), Krishna C. Vadodaria (USA), Paul Bangirana (Uganda) and Wei Shi (China) - have been selected to share their research on novel experimental approaches in treating infectious and environmental diseases affecting the nervous system. Please attend this premier event!
IBRO ALUMNI SfN SYMPOSIUM
Novel experimental approaches to treat infectious and environmental diseases affecting the nervous system
Monday, 14 November 2016, from 18:30 - 21:00 – Marriott Marquis San Diego Marina, San Diego Ballroom C
Most diseases affecting the nervous system are caused by a combination of genetic and environmental factors or by infections. In this symposium five distinguished IBRO Alumni will present state-of-the-art molecular and clinical approaches aimed at reversing clinical phenotypes induced by infectious and environmental agents.
Nidogens are new therapeutic targets for the prevention of tetanus
Kinga Bercsenyi1,2, Nathalie Schmieg1,2, J. Barney Bryson2, Paola Caccin3, Matthew Golding1, Giuseppe Zanotti3, Linda Greensmith2, Roswitha Nischt4 and Giampietro Schiavo2
1Molecular Neuropathobiology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London, WC2A 3LY, UK;
2Sobell Department of Motor Neuroscience & Movement Disorders, UCL Institute of Neurology, University College London, WC1N 3BG London, UK;
3Department of Biomedical Sciences, University of Padua, Viale G. Colombo 3, 35131 Padova, Italy;
4Department of Dermatology, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany
Tetanus neurotoxin (TeNT) is among the most poisonous substances on Earth and a major cause of neonatal death in non-vaccinated areas. There are approximately 300,000 cases reported worldwide each year, and the mortality rate is between 10-20%. I identified an extracellular matrix protein receptor for TeNT at the neuromuscular junction (NMJ) and developed a peptide inhibitor, which prevents tetanic paralysis in vivo in mice. TeNT binds to the NMJ with an extremely high affinity, yet the nature of its receptor complex was poorly understood. I showed that the presence of nidogens (also known as entactins) at the NMJ is the main determinant for TeNT binding. Nidogens are extracellular matrix (ECM) proteins, which are taken up into the endosomal carriers containing tetanus toxin binding fragment (HCT) in motor neurons. Inhibition of the HCT-nidogen interaction using a peptide originating from nidogen-1 abolishes HCT binding on these cells.
TeNT causes slowly progressing local tetanus when it is injected intramuscularly into the triceps surae muscle in a low dose. When preincubated with the peptide originating from nidogen-1, TeNT injection does not alter the coordination of mice and the muscle force remains largely unchanged. Genetic ablation of nidogens prevents the binding of TeNT to neurons and the intact NMJ and protects mice from TeNT induced spastic paralysis.
Here, I demonstrate for the first time, that an ECM protein accumulates and presents a neurotropic pathogen to the presynapse. This study follows recent studies showing that growth factors trigger downstream signalling more efficiently if they bind to certain ECM components – a new and rising concept in neuroscience.
Neuro-immune interactions in the sensory ganglia account for herpetic pain
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Brazil
Herpetic neuralgia is the most important symptom of herpes zoster disease, which is caused by Varicella zoster. Here, we examine the neuro-immune interaction in the sensory ganglia that account for the genesis of herpetic pain by using a murine model of Herpes simplex virus type-1 (HSV-1) infection. The cutaneous HSV-1 infection of mice results in the development of a zosteriform-like skin lesion followed by a time-dependent increase in pain-like responses (mechanical allodynia). Leukocytes, composed mainly of macrophages and neutrophils, infiltrate infected DRGs and account for the development of herpetic pain-like behavior. Infiltrating leukocytes are responsible for driving the production of TNF-α, which in turn mediates the genesis of herpetic neuralgia through down-regulation of the inwardly rectifying K+ channel, Kir4.1, in satellite glial cells. These results revealed for the first time that neuro-immune interactions at the sensory ganglia are involved in the genesis of herpetic neuralgia. In conclusion, the present study elucidates novel mechanisms involved in the genesis of herpetic pain and open new avenues in its control.
Inhaled nitric oxide improves neurocognitive outcomes in children with severe malaria and lactic acidosis
Paul Bangirana1, Andrea L. Conroy2,3, Robert O. Opoka4, Michael Hawkes2,5, Laura Hermann2, Christopher Miller6, Sophie Namasopo7, W. Conrad Liles8, Chandy C. John2, Kevin C. Kain2
1Makerere University College of Health Sciences, Kampala, Uganda;
2University of Toronto, Toronto, Canada;
3Indiana University School of Medicine, Indianapolis, USA;
4Makerere University College of Health Sciences, Kampala, Uganda;
5University of Alberta, Edmonton, Canada;
6University of British Columbia, Vancouver, Canada;
7Jinja Regional Referral Hospital, Jinja, Uganda;
8University of Washington, Seattle, WA, 98195, USA
Severe malaria is a leading cause of neurocognitive impairment in African children. Low levels of bioavailable nitric oxide (NO) are associated with severe malaria. Supplementation with inhaled NO (iNO) has been shown to be neuroprotective in term or near-term infants with persistent pulmonary hypertension but the neuroprotective actions of iNO have not been documented in systemic infections. This randomized, double-blind, placebo-controlled trial compared the effect of inhaled nitric oxide (iNO) at 80ppm versus room air (placebo) on neurocognitive function in children with severe malaria treated with parenteral artesunate. Children aged 1 to 10 years received either iNO or placebo. Six months post-discharge, neurocognitive testing was performed to assess overall cognition, attention, associative memory, executive function, motor skills, language and visual reception. We compared test scores between the treatment arms and the frequency of impairment in all domains between the arms. Our results showed that at six months, 61 children in the iNO arm and 59 children in the placebo arm were evaluated. 35% of children had impairment (defined by a z-score ≤-2SD) in at least one domain. There were no significant differences in z-scores for overall cognition, attention, associative memory and executive function between iNO and the placebo group. Children receiving iNO were less likely to have multiple impaired domains (11.5% vs 25.4%, p=0.048) and to have fine motor impairment, relative to children receiving placebo (8.2% vs 22.0%, p=0.034). Subgroup analysis in children with acidosis at admission showed iNO was associated with improved attention (p=0.001), fine motor functioning (p=0.004), visual reception (p=0.028), receptive language (p=0.015), and overall cognitive function (p=0.009).
In conclusion, inhaled nitric oxide is associated with better cognitive outcomes in children with severe malaria presenting with acidosis.
Human stem cell technology to study serotonergic neurotransmission in neuropsychiatric disorders
Krishna C. Vadodaria and Fred H. Gage
Salk Institute for Biological Studies, La Jolla, CA, USA
The brain’s serotonergic system centrally regulates several physiological processes and its dysfunction has been implicated in the pathophysiology of several neuropsychiatric disorders including major depression. While in the past our understanding of serotonergic neurotransmission has come mainly from mouse models, the development of pluripotent stem cell and induced fibroblast-to-neuron (iN) transdifferentiation technologies has revolutionized our ability to generate human neurons in vitro. Utilizing these techniques and a novel lentiviral reporter for serotonergic neurons, we identified and overexpressed key transcription factors to successfully generate human serotonergic neurons. We found that overexpressing the transcription factors NKX2.2, FEV, GATA2, LMX1B in combination with ASCL1 and NGN2 directly and efficiently generated serotonergic that displayed spontaneous action potentials, released serotonin in vitro, and functionally responded to selective serotonin reuptake inhibitors (SSRIs). We demonstrate a method to efficiently generate human serotonergic neurons in vitro, with the potential to study serotonergic neurotransmission in patients with neuropsychiatric disorders such as Major Depression.
Rapid memory dissipation in Alzheimer’s disease can be ameliorated by reducing Rac1 activity.
Wei SHI, Wenjuan WU, Shuwen DU, Ying HU, Yunlong LIU, YI Zhong
Key Laboratory for Protein Sciences of Ministry of Education, School of Life Sciences, Tsinghua University, Beijing 1000084, China
Memory loss that disrupts daily life is a major symptom of Alzheimer's disease (AD), especially for newly-formed memory. There is mounting evidence that Aβ42 could activate Rac1, a small G protein, through several cascades in vitro and in vivo; however the function of this activation is still obscure. Shuai (2010) reported in Drosophila that Rac1 could regulate forgetting of short-term memory. We speculate that activation of Rac1 in AD may mediate abnormal forgetting leading to memory loss. Here, we first detected the changes of activation of Rac1 in AD fly and mice as well as in lysis of AD patient’s hippocampus. Significantly higher levels of Rac1-GTP were observed as previous studies. Then we manipulated Rac1 activity by pharmaceutical and genetic approaches in AD fly and mice, and found that the defect of memory and synaptic plasticity could be ameliorated. Furthermore, according to the study by Wang (2012), Aβ42 may initiate EGFR/PI3K/Akt axis which is upstream of Rac1 to exert its pathological function. We found Gefitinib, an inhibitor of EGFR, could rescue synaptic defect in vitro and memory loss in vivo. Finally, to explain why forgetting is accelerated in AD, we detected spatial working memory in AD models and found more rapid memory decay after couple of minutes in mice compared with control. Together, we found Aβ42 could accelerate forgetting by evoking Rac1 through EGFR pathway and impair LTP maintenance. We provide a new angle to study the pathological mechanism of AD. Inhibition of forgetting via Rac1 may be a new therapeutic intervention in AD treatment.