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  1. Article ; Online: A role for endothelial NMDA receptors in the pathophysiology of schizophrenia.

    Intson, Katheron / Geissah, Salma / McCullumsmith, Robert E / Ramsey, Amy J

    Schizophrenia research

    2020  Volume 249, Page(s) 63–73

    Abstract: Numerous genetic and postmortem studies link N-methyl-d-aspartate receptor (NMDAR) dysfunction with schizophrenia, forming the basis of the popular glutamate hypothesis. Neuronal NMDAR abnormalities are consistently reported from both basic and clinical ... ...

    Abstract Numerous genetic and postmortem studies link N-methyl-d-aspartate receptor (NMDAR) dysfunction with schizophrenia, forming the basis of the popular glutamate hypothesis. Neuronal NMDAR abnormalities are consistently reported from both basic and clinical experiments, however, non-neuronal cells also contain NMDARs, and are rarely, if ever, considered in the discussion of glutamate action in schizophrenia. We offer an examination of recent discoveries elucidating the actions and consequences of NMDAR activation in the neuroendothelium. While there has been mixed literature regarding blood flow alterations in the schizophrenia brain, in this review, we posit that some common findings may be explained by neuroendothelial NMDAR dysfunction. In particular, we emphasize that endothelial NMDARs are key mediators of neurovascular coupling, where increased neuronal activity leads to increased blood flow. Based on the broad conclusions that hypoperfusion is a neuroanatomical finding in schizophrenia, we discuss potential mechanisms by which endothelial NMDARs contribute to this disorder. We propose that endothelial NMDAR dysfunction can be a primary cause of neurovascular abnormalities in schizophrenia. Importantly, functional MRI studies using BOLD signal as a proxy for neuron activity should be considered in a new light if neurovascular coupling is impaired in schizophrenia. This review is the first to propose that NMDARs in non-excitable cells play a role in schizophrenia.
    MeSH term(s) Humans ; Receptors, N-Methyl-D-Aspartate/metabolism ; Schizophrenia/diagnostic imaging ; Glutamic Acid ; Aspartic Acid ; Brain
    Chemical Substances Receptors, N-Methyl-D-Aspartate ; Glutamic Acid (3KX376GY7L) ; Aspartic Acid (30KYC7MIAI)
    Language English
    Publishing date 2020-11-11
    Publishing country Netherlands
    Document type Review ; Journal Article
    ZDB-ID 639422-x
    ISSN 1573-2509 ; 0920-9964
    ISSN (online) 1573-2509
    ISSN 0920-9964
    DOI 10.1016/j.schres.2020.10.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2351: Show issues Location:
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  2. Article ; Online: An independent appraisal and re-analysis of hydroxychloroquine treatment trial for COVID-19.

    Intson, Katheron / Kumar, Sachin / Botta, Amy / Neckles, Rachael / Leung, Connie / Jawaid, Ali

    Swiss medical weekly

    2020  Volume 150, Page(s) w20262

    MeSH term(s) Adult ; Azithromycin/therapeutic use ; Betacoronavirus ; Clinical Trials as Topic ; Coronavirus Infections/drug therapy ; Data Accuracy ; Drug Synergism ; Drug Therapy, Combination ; France ; Humans ; Hydroxychloroquine/therapeutic use ; Middle Aged ; Pandemics ; Pneumonia, Viral/drug therapy ; Research Design
    Chemical Substances Hydroxychloroquine (4QWG6N8QKH) ; Azithromycin (83905-01-5)
    Keywords covid19
    Language English
    Publishing date 2020-04-29
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2036179-8
    ISSN 1424-3997 ; 1424-7860
    ISSN (online) 1424-3997
    ISSN 1424-7860
    DOI 10.4414/smw.2020.20262
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: An independent appraisal and re-analysis of hydroxychloroquine treatment trial for COVID-19

    Intson, Katheron / Kumar, Sachin / Botta, Amy / Neckles, Rachael / Leung, Connie / Jawaid, Ali

    Swiss Med Wkly

    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #141760
    Database COVID19

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  4. Article ; Online: An independent appraisal and re-analysis of hydroxychloroquine treatment trial for COVID-19

    Intson, Katheron / Kumar, Sachin / Botta, Amy / Neckles, Rachael / Leung, Connie / Jawaid, Ali

    Swiss Medical Weekly ; ISSN 1424-3997

    2020  

    Keywords General Medicine ; covid19
    Language English
    Publisher EMH Swiss Medical Publishers, Ltd.
    Publishing country ch
    Document type Article ; Online
    DOI 10.4414/smw.2020.20262
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Chronic social isolation exerts opposing sex-specific consequences on serotonin neuronal excitability and behaviour.

    Oliver, David K / Intson, Katheron / Sargin, Derya / Power, Saige K / McNabb, Janice / Ramsey, Amy J / Lambe, Evelyn K

    Neuropharmacology

    2020  Volume 168, Page(s) 108015

    Abstract: Social isolation raises the risk for mood disorders associated with serotonergic disruption. Yet, the underlying mechanisms by which the stress of social isolation increases risk are not well understood. Men and women are differently vulnerable; however, ...

    Abstract Social isolation raises the risk for mood disorders associated with serotonergic disruption. Yet, the underlying mechanisms by which the stress of social isolation increases risk are not well understood. Men and women are differently vulnerable; however, this modulating role of sex is challenging to study in humans under carefully controlled conditions. Therefore, we investigated this question in mice of both sexes, asking how the long-term stress of social isolation (from weaning into adulthood) affects the excitability of serotonin neurons in the dorsal raphe nucleus as well as mouse behaviour. The electrophysiological experiments and the first set of behavioural tests were conducted in young adult mice, with additional behavioural assays completed as the mice matured to assess the stability of their behavioural phenotype. We found that social isolation exerted seemingly-opposite effects in male and female mice, relative to their respective group-housed littermate controls. This distinctive pattern was observed for the effect of social isolation on the control of serotonergic neuron excitability via the SK family of calcium-activated potassium channels. Furthermore, we observed a similar and consistent pattern on tests relevant to assessing the efficacy of anti-depressant medicines, including the forced swim test, the novelty-suppressed feeding test, and the sucrose preference test. These findings underscore the concept that stress-elicited illness manifests distinctly in males and females and that treatments aimed at restoring serotonergic function may require a sex-specific approach. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
    MeSH term(s) Animals ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Potassium Channel Blockers/pharmacology ; Potassium Channels, Calcium-Activated/antagonists & inhibitors ; Potassium Channels, Calcium-Activated/metabolism ; Serotonergic Neurons/drug effects ; Serotonergic Neurons/metabolism ; Serotonin/metabolism ; Sex Characteristics ; Social Isolation/psychology
    Chemical Substances Potassium Channel Blockers ; Potassium Channels, Calcium-Activated ; Serotonin (333DO1RDJY)
    Language English
    Publishing date 2020-02-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218272-5
    ISSN 1873-7064 ; 0028-3908
    ISSN (online) 1873-7064
    ISSN 0028-3908
    DOI 10.1016/j.neuropharm.2020.108015
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    Ui I Zs.242: Show issues Location:
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  6. Article ; Online: Opposing Cholinergic and Serotonergic Modulation of Layer 6 in Prefrontal Cortex.

    Sparks, Daniel W / Tian, Michael K / Sargin, Derya / Venkatesan, Sridevi / Intson, Katheron / Lambe, Evelyn K

    Frontiers in neural circuits

    2018  Volume 11, Page(s) 107

    Abstract: Prefrontal cortex is a hub for attention processing and receives abundant innervation from cholinergic and serotonergic afferents. A growing body of evidence suggests that acetylcholine (ACh) and serotonin (5-HT) have opposing influences on tasks ... ...

    Abstract Prefrontal cortex is a hub for attention processing and receives abundant innervation from cholinergic and serotonergic afferents. A growing body of evidence suggests that acetylcholine (ACh) and serotonin (5-HT) have opposing influences on tasks requiring attention, but the underlying neurophysiology of their opposition is unclear. One candidate target population is medial prefrontal layer 6 pyramidal neurons, which provide feedback modulation of the thalamus, as well as feed-forward excitation of cortical interneurons. Here, we assess the response of these neurons to ACh and 5-HT using whole cell recordings in acute brain slices from mouse cortex. With application of exogenous agonists, we show that individual layer 6 pyramidal neurons are bidirectionally-modulated, with ACh and 5-HT exerting opposite effects on excitability across a number of concentrations. Next, we tested the responses of layer 6 pyramidal neurons to optogenetic release of endogenous ACh or 5-HT. These experiments were performed in brain slices from transgenic mice expressing channelrhodopsin in either ChAT-expressing cholinergic neurons or Pet1-expressing serotonergic neurons. Light-evoked endogenous neuromodulation recapitulated the effects of exogenous neurotransmitters, showing opposing modulation of layer 6 pyramidal neurons by ACh and 5-HT. Lastly, the addition of 5-HT to either endogenous or exogenous ACh significantly suppressed the excitation of pyramidal neurons in prefrontal layer 6. Taken together, this work suggests that the major corticothalamic layer of prefrontal cortex is a substrate for opposing modulatory influences on neuronal activity that could have implications for regulation of attention.
    MeSH term(s) Acetylcholine/metabolism ; Action Potentials/drug effects ; Action Potentials/physiology ; Animals ; Cholinergic Agents/pharmacology ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurons/drug effects ; Neurons/metabolism ; Optogenetics ; Patch-Clamp Techniques ; Prefrontal Cortex/anatomy & histology ; Prefrontal Cortex/drug effects ; Prefrontal Cortex/metabolism ; Serotonin/metabolism ; Serotonin Agents/pharmacology ; Tissue Culture Techniques
    Chemical Substances Cholinergic Agents ; Serotonin Agents ; Serotonin (333DO1RDJY) ; Acetylcholine (N9YNS0M02X)
    Language English
    Publishing date 2018-01-04
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2452968-0
    ISSN 1662-5110 ; 1662-5110
    ISSN (online) 1662-5110
    ISSN 1662-5110
    DOI 10.3389/fncir.2017.00107
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  7. Article ; Online: Progressive neuroanatomical changes caused by Grin1 loss-of-function mutation.

    Intson, Katheron / van Eede, Matthijs C / Islam, Rehnuma / Milenkovic, Marija / Yan, Yuanye / Salahpour, Ali / Henkelman, R Mark / Ramsey, Amy J

    Neurobiology of disease

    2019  Volume 132, Page(s) 104527

    Abstract: NMDA receptor dysfunction is central to the encephalopathies caused by missense mutations in the NMDA receptor subunit genes. Missense variants of GRIN1, GRIN2A, and GRIN2B cause similar syndromes with varying severity of intellectual impairment, autism, ...

    Abstract NMDA receptor dysfunction is central to the encephalopathies caused by missense mutations in the NMDA receptor subunit genes. Missense variants of GRIN1, GRIN2A, and GRIN2B cause similar syndromes with varying severity of intellectual impairment, autism, epilepsy, and motor dysfunction. To gain insight into possible biomarkers of NMDAR hypofunction, we asked whether a loss-of-function variant in the Grin1 gene would cause structural changes in the brain that could be detected by MRI. We also studied the developmental trajectory of these changes to determine whether structural changes coincided with reported cognitive impairments in the mice. We performed magnetic resonance imaging in male Grin1-/- knockdown mice (GluN1KD) that were three, six, or twelve weeks old. Deformation-based morphometry was used to assess neuroanatomical differences. Volumetric reductions were detected in substantia nigra and striatum of GluN1KD mice at all ages. Changes in limbic structures were only evident at six weeks of age. Reductions in white matter volumes were first evident at three weeks, and additional deficits were detected at six and twelve weeks. FluoroJade immunofluorescence revealed degenerating neurons in twelve-week old GluN1KD mice. We conclude that Grin1 loss-of-function mutations cause volume reductions in dopaminergic structures early in development, while changes to limbic and white matter structures are delayed and are more pronounced in post-adolescent ages. The evidence of degenerating neurons in the mature brain indicates an ongoing process of cell loss as a consequence of NMDAR hypofunction.
    MeSH term(s) Age Factors ; Animals ; Brain/anatomy & histology ; Brain/diagnostic imaging ; Brain/growth & development ; Dopaminergic Neurons/physiology ; Loss of Function Mutation/genetics ; Male ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Transgenic ; Nerve Tissue Proteins/genetics ; Organ Size/physiology ; Receptors, N-Methyl-D-Aspartate/genetics
    Chemical Substances Gprin1 protein, mouse ; Nerve Tissue Proteins ; Receptors, N-Methyl-D-Aspartate
    Language English
    Publishing date 2019-07-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1211786-9
    ISSN 1095-953X ; 0969-9961
    ISSN (online) 1095-953X
    ISSN 0969-9961
    DOI 10.1016/j.nbd.2019.104527
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    Zs.A 4444: Show issues Location:
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  8. Article ; Online: Consequences of NMDA receptor deficiency can be rescued in the adult brain.

    Mielnik, Catharine A / Binko, Mary A / Chen, Yuxiao / Funk, Adam J / Johansson, Emily M / Intson, Katheron / Sivananthan, Nirun / Islam, Rehnuma / Milenkovic, Marija / Horsfall, Wendy / Ross, Ruth A / Groc, Laurent / Salahpour, Ali / McCullumsmith, Robert E / Tripathy, Shreejoy / Lambe, Evelyn K / Ramsey, Amy J

    Molecular psychiatry

    2020  Volume 26, Issue 7, Page(s) 2929–2942

    Abstract: N-methyl-D-aspartate receptors (NMDARs) are required to shape activity-dependent connections in the developing and adult brain. Impaired NMDAR signalling through genetic or environmental insults causes a constellation of neurodevelopmental disorders that ...

    Abstract N-methyl-D-aspartate receptors (NMDARs) are required to shape activity-dependent connections in the developing and adult brain. Impaired NMDAR signalling through genetic or environmental insults causes a constellation of neurodevelopmental disorders that manifest as intellectual disability, epilepsy, autism, or schizophrenia. It is not clear whether the developmental impacts of NMDAR dysfunction can be overcome by interventions in adulthood. This question is paramount for neurodevelopmental disorders arising from mutations that occur in the GRIN genes, which encode NMDAR subunits, and the broader set of mutations that disrupt NMDAR function. We developed a mouse model where a congenital loss-of-function allele of Grin1 can be restored to wild type by gene editing with Cre recombinase. Rescue of NMDARs in adult mice yields surprisingly robust improvements in cognitive functions, including those that are refractory to treatment with current medications. These results suggest that neurodevelopmental disorders arising from NMDAR deficiency can be effectively treated in adults.
    MeSH term(s) Alleles ; Animals ; Brain/metabolism ; Gene Editing ; Loss of Function Mutation ; Mice ; Nerve Tissue Proteins/genetics ; Receptors, N-Methyl-D-Aspartate/genetics ; Receptors, N-Methyl-D-Aspartate/metabolism
    Chemical Substances Gprin1 protein, mouse ; Nerve Tissue Proteins ; Receptors, N-Methyl-D-Aspartate
    Language English
    Publishing date 2020-08-17
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1330655-8
    ISSN 1476-5578 ; 1359-4184
    ISSN (online) 1476-5578
    ISSN 1359-4184
    DOI 10.1038/s41380-020-00859-4
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