Glutamate signalling: A multifaceted modulator of oligodendrocyte lineage cells in health and disease.

Myelin is essential for the mammalian brain to function efficiently. Whilst many factors have been associated with regulating the differentiation of oligodendroglia and myelination, glutamate signalling might be particularly important for learning-dependent myelination. The majority of myelinated projection neurons are glutamatergic. Oligodendrocyte precursor cells receive glutamatergic synaptic inputs from unmyelinated axons and oligodendrocyte lineage cells express glutamate receptors which enable them to monitor and respond to changes in neuronal activity. Yet, what role glutamate plays for oligodendroglia is not fully understood. Here, we review glutamate signalling and its effects on oligodendrocyte lineage cells, and myelination in health and disease. Furthermore, we discuss whether glutamate signalling between neurons and oligodendroglia might lay the foundation to activity-dependent white matter plasticity. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'.Lister Institute of Preventive Medicine: Ragnhildur Thóra Káradóttir and Sonia Spitzer; Wellcome Trust: Ragnhildur Thóra Káradóttir 091543/Z/10/Z; Medical Research Council: Katrin Volbracht: DTG RG64862; Sonia Spitzer: 1004208.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.neuropharm.2016.06.01

Peer Deviance, Social Support, and Symptoms of Internalizing Disorders among Youth Exposed to Hurricane Georges

This study examined the influence of peers in meeting DSM-IV symptom criteria for an internalizing disorder in adolescents exposed to Hurricane Georges. Participants included a representative community sample of 905 youth (N = 476 boys) ages 11-17 residing in Puerto Rico. Data were gathered on hurricane exposure, symptoms of internalizing disorders, peer social support, peer violence, and peer substance use through in-person structured interviews with adolescents and caretakers from 1999-2000 in Puerto Rico, 12-27 months after Hurricane Georges. Hurricane exposure, peer violence, and peer substance use predicted whether adolescents met DSM-IV symptom criteria for a measured internalizing disorder. An interaction was found between hurricane exposure and peer violence, which indicated that hurricane exposure was significantly related to meeting DSM-IV symptom criteria for an internalizing disorder among adolescents who do not report associating with violent peers. However, for participants who reported high levels of peer violence, hurricane exposure did not convey additional risk for meeting DSM-IV symptom criteria for an internalizing disorder. With the increasing role peers play in adolescents’ lives, understanding the influence of peers on the development of internalizing symptoms following hurricane exposure may assist in planning developmentally sensitive response plans

Oligodendrocyte progenitor cells become regionally diverse and heterogeneous with age

Oligodendrocyte progenitor cells (OPCs), which differentiate into myelinating oligodendrocytes during central nervous system (CNS) development, are the main proliferative cells in the adult brain. OPCs are conventionally considered a homogeneous population, particularly with respect to their electrophysiological properties, but this has been debated. We show, by using single-cell electrophysiological recordings, that OPCs start out as a homogeneous population, but become functionally heterogeneous, varying both within and between brain regions and with age. These electrophysiological changes in OPCs correlate with the differentiation potential of OPCs; thus, they may underlie the differentiational differences in OPCs between regions and likewise differentiation failure with age.We acknowledge the support of the Wellcome - MRC Cambridge Stem Cell Institute core facility managers, in particular for this work Dr Maike Paramor and Miss Victoria Murray with RNA sequencing, and all staff members of the University Biomedical Services (UBS). This project has received funding from: the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 771411; R.T.K, K.A.E); the Wellcome Trust, a Research Career Development Fellowship (R.T.K. and K.A.E. 091543/Z/10/Z) and a Studentship (102160/Z/13/Z; Y.K); The Paul G Allen Frontiers Group, Allen Distinguished Investigator Award (12076, R.T.K., D.K.V.); The Medical Research Council, a studentship (S.O.S.); The Gates Foundation, a Gates Scholarship (S.S.), The Biotechnology and Biological Sciences Research Council, a studentship (S.A.); Homerton College Cambridge, a Junior Research Fellowship (D.K.V); The UK MS Society, a Cambridge Myelin Repair Centre grant (50; R.T.K, O.D.F.); The Fonds de recherche du Québec-Santé, a scholarship (Y.K.); The Cambridge Commonwealth European & International Trust, a scholarship (Y.K.); and the Lister Institute, a Research Prize (R.T.K., K.A.E, SOS)

Oligodendrocyte Progenitor Cells Become Regionally Diverse and Heterogeneous with Age

We thank J. Trotter (Johannes Gutenberg University, Mainz, Germany) for the NG2-EYFP mice, Dr. Moritz Matthey for help with minipump transplantation, Miss Mariann Kovacs with embryonic dissection, and Dr. Katrin Volbracht for critical comments on the work. We acknowledge the support of the Wellcome – MRC Cambridge Stem Cell Institute core facility managers, in particular for this work Dr. Maike Paramor and Miss Victoria Murray with RNA-seq, and all staff members of the University Biomedical Services (UBS). This project has received the following funding: funding from the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Program (grant agreement 771411 to R.T.K. and K.A.E.), a Wellcome Trust research career development fellowship (091543/Z/10/Z to R.T.K. and K.A.E.) and studentship (102160/Z/13/Z to Y.K.), Paul G. Allen Frontiers Group Allen Distinguished Investigator Award 12076 (to R.T.K., D.K.-V., and K.A.E.), a Medical Research Council studentship (to S.O.S.), a Gates Cambridge Trust Gates scholarship (to S.S.), a Biotechnology and Biological Sciences Research Council studentship (to S.A.), a Homerton College Cambridge junior research fellowship (to D.K.-V.), UK MS Society Cambridge Myelin Repair Centre grant 50 (to R.T.K. and O.d.F.), a Fonds de Recherche du Québec - Santé scholarship (to Y.K.), a Cambridge Commonwealth, European and International Trust scholarship (to Y.K.), and a Lister Institute research prize (to R.T.K., K.A.E., and S.O.S.). Publisher Copyright: © 2018 The Author(s)Spitzer et al. show that oligodendrocyte progenitor cells (OPCs) acquire ion channels and sensitivity to neuronal activity that differ between region and age. The onset and decline of ion channels follow developmental milestones. This heterogeneity indicates different functional states of OPCs.Peer reviewe

Developmental signatures of microbiota-derived metabolites in the mouse brain

The gut microbiome is recognized to exert a wide-ranging influence on host health and disease, including brain development and behavior. Commensal bacteria can produce bioactive molecules that enter the circulation and impact host physiology and homeostasis. However, little is known about the potential for these metabolites to cross the blood-brain barrier and enter the developing brain under normal physiological conditions. In this study, we used a liquid chromatography-mass spectrometry-based metabolomic approach to characterize the developmental profiles of microbial-derived metabolites in the forebrains of mice across three key postnatal developmental stages, co-occurring with the maturation of the gut microbiota. We demonstrate that direct metabolites of the gut microbiome (e.g., imidazole propionate) or products of the combinatorial metabolism between the microbiome and host (e.g., 3-indoxyl-sulfate, trimethylamine-N-oxide, and phenylacetylglycine) are present in the forebrains of mice as early as the neonatal period and remain into adulthood. These findings demonstrate that microbial-associated molecules can cross the BBB either in their detected form or as precursor molecules that undergo further processing in the brain. These chemical messengers are able to bind receptors known to be expressed in the brain. Alterations in the gut microbiome may therefore influence neurodevelopmental trajectories via the regulation of these microbial-associated metabolites.</p

Gene Editing in Rat Embryonic Stem Cells to Produce In Vitro Models and In Vivo Reporters

Rat embryonic stem cells (ESCs) offer the potential for sophisticated genome engineering in this valuable biomedical model species. However, germline transmission has been rare following conventional homologous recombination and clonal selection. Here, we used the CRISPR/Cas9 system to target genomic mutations and insertions. We first evaluated utility for directed mutagenesis and recovered clones with biallelic deletions in Lef1. Mutant cells exhibited reduced sensitivity to glycogen synthase kinase 3 inhibition during self-renewal. We then generated a non-disruptive knockin of dsRed at the Sox10 locus. Two clones produced germline chimeras. Comparative expression of dsRed and SOX10 validated the fidelity of the reporter. To illustrate utility, live imaging of dsRed in neonatal brain slices was employed to visualize oligodendrocyte lineage cells for patch-clamp recording. Overall, these results show that CRISPR/Cas9 gene editing technology in germline-competent rat ESCs is enabling for in vitro studies and for generating genetically modified rats

Clemastine and metformin extend the window of NMDA receptor surface expression in ageing oligodendrocyte precursor cells

Funder: Lister Institute of Preventive MedicineFunder: Fonds de Recherche du Qu&#x00E9;bec - Sant&#x00E9; (Fonds de la recherche en sante du Quebec)Funder: Cambridge Commonwealth, European and International Trust (Cambridge Commonwealth, European & International Trust)Funder: Gates Cambridge TrustAbstractIn the central nervous system, oligodendrocyte precursor cells (OPCs) proliferate and differentiate into myelinating oligodendrocytes throughout life, allowing for ongoing myelination and myelin repair. With age, differentiation efficacy decreases and myelin repair fails; therefore, recent therapeutic efforts have focused on enhancing differentiation. Many cues are thought to regulate OPC differentiation, including neuronal activity, which OPCs can sense and respond to via their voltage-gated ion channels and glutamate receptors. However, OPCs’ density of voltage-gated ion channels and glutamate receptors differs with age and brain region, and correlates with their proliferation and differentiation potential, suggesting that OPCs exist in different functional cell states, and that age-associated states might underlie remyelination failure. Here, we use whole-cell patch-clamp to investigate whether clemastine and metformin, two pro-remyelination compounds, alter OPC membrane properties and promote a specific OPC state. We find that clemastine and metformin extend the window of NMDAR surface expression, promoting an NMDAR-rich OPC state. Our findings highlight a possible mechanism for the pro-remyelinating action of clemastine and metformin, and suggest that OPC states can be modulated as a strategy to promote myelin repair.</jats:p

Clemastine and metformin extend the window of NMDA receptor surface expression in ageing oligodendrocyte precursor cells

Abstract In the central nervous system, oligodendrocyte precursor cells (OPCs) proliferate and differentiate into myelinating oligodendrocytes throughout life, allowing for ongoing myelination and myelin repair. With age, differentiation efficacy decreases and myelin repair fails; therefore, recent therapeutic efforts have focused on enhancing differentiation. Many cues are thought to regulate OPC differentiation, including neuronal activity, which OPCs can sense and respond to via their voltage-gated ion channels and glutamate receptors. However, OPCs’ density of voltage-gated ion channels and glutamate receptors differs with age and brain region, and correlates with their proliferation and differentiation potential, suggesting that OPCs exist in different functional cell states, and that age-associated states might underlie remyelination failure. Here, we use whole-cell patch-clamp to investigate whether clemastine and metformin, two pro-remyelination compounds, alter OPC membrane properties and promote a specific OPC state. We find that clemastine and metformin extend the window of NMDAR surface expression, promoting an NMDAR-rich OPC state. Our findings highlight a possible mechanism for the pro-remyelinating action of clemastine and metformin, and suggest that OPC states can be modulated as a strategy to promote myelin repair

Postnatal prebiotic supplementation in rats affects adult anxious behaviour, hippocampus, electrophysiology, metabolomics, and gut microbiota

Summary: We have shown previously that prebiotic (Bimuno galacto-oligosacharides, B-GOS®) administration to neonatal rats increased hippocampal NMDAR proteins. The present study has investigated the effects of postnatal B-GOS® supplementation on hippocampus-dependent behavior in young, adolescent, and adult rats and applied electrophysiological, metabolomic and metagenomic analyses to explore potential underlying mechanisms. The administration of B-GOS® to suckling, but not post-weaned, rats reduced anxious behavior until adulthood. Neonatal prebiotic intake also reduced the fast decay component of hippocampal NMDAR currents, altered age-specific trajectories of the brain, intestinal, and liver metabolomes, and reduced abundance of fecal Enterococcus and Dorea bacteria. Our data are the first to show that prebiotic administration to rats during a specific postnatal period has long-term effects on behavior and hippocampal physiology. The study also suggests that early-life prebiotic intake may affect host brain function through the reduction of stress-related gut bacteria rather than increasing the proliferation of beneficial microbes