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  1. Article ; Online: A clinically relevant selective ERK-pathway inhibitor reverses core deficits in a mouse model of autismResearch in context

    Kartikeya Murari / Abdulrahman Abushaibah / Jong M. Rho / Ray W. Turner / Ning Cheng

    EBioMedicine, Vol 91, Iss , Pp 104565- (2023)

    2023  

    Abstract: Summary: Background: Extracellular signal-regulated kinase (ERK/MAPK) pathway in the brain is hypothesized to be a critical convergent node in the development of autism spectrum disorder. We reasoned that selectively targeting this pathway could reverse ... ...

    Abstract Summary: Background: Extracellular signal-regulated kinase (ERK/MAPK) pathway in the brain is hypothesized to be a critical convergent node in the development of autism spectrum disorder. We reasoned that selectively targeting this pathway could reverse core autism-like phenotype in animal models. Methods: Here we tested a clinically relevant, selective inhibitor of ERK pathway, PD325901 (Mirdametinib), in a mouse model of idiopathic autism, the BTBR mice. Findings: We report that treating juvenile mice with PD325901 reduced ERK pathway activation, dose and duration-dependently reduced core disease-modeling deficits in sociability, vocalization and repetitive behavior, and reversed abnormal EEG signals. Further analysis revealed that subchronic treatment did not affect weight gain, locomotion, or neuronal density in the brain. Parallel treatment in the C57BL/6J mice did not alter their phenotype. Interpretation: Our data indicate that selectively inhibiting ERK pathway using PD325901 is beneficial in the BTBR model, thus further support the notion that ERK pathway is critically involved in the pathophysiology of autism. These results suggest that a similar approach could be applied to animal models of syndromic autism with dysregulated ERK signaling, to further test selectively targeting ERK pathway as a new approach for treating autism. Funding: : This has beenwork was supported by Alberta Children’s Hospital Research Foundation (JMR & NC), University of Calgary Faculty of Veterinary Medicine (NC), Kids Brain Health Network (NC), and Natural Sciences and Engineering Research Council of Canada (NC).
    Keywords Autism ; ERK ; Selective inhibitor ; PD325901/Mirdametinib ; Repurposed drug ; EEG ; Medicine ; R ; Medicine (General) ; R5-920
    Subject code 616
    Language English
    Publishing date 2023-05-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Junctophilin Proteins Tether a Cav1-RyR2-KCa3.1 Tripartite Complex to Regulate Neuronal Excitability

    Giriraj Sahu / Rima-Marie Wazen / Pina Colarusso / S.R. Wayne Chen / Gerald W. Zamponi / Ray W. Turner

    Cell Reports, Vol 28, Iss 9, Pp 2427-2442.e

    2019  Volume 6

    Abstract: Summary: The excitability of CA1 hippocampal pyramidal cells is mediated by a slow AHP (sAHP) that responds to calcium increases by Cav1 calcium channels and ryanodine receptors (RyR). We used super-resolution and FRET microscopy to investigate the ... ...

    Abstract Summary: The excitability of CA1 hippocampal pyramidal cells is mediated by a slow AHP (sAHP) that responds to calcium increases by Cav1 calcium channels and ryanodine receptors (RyR). We used super-resolution and FRET microscopy to investigate the proximity and functional coupling among Cav1.3/Cav1.2, RyR2, and KCa3.1 potassium channels that contribute to the sAHP. dSTORM and FRET imaging shows that Cav1.3, RyR2, and KCa3.1 are organized as a triprotein complex that colocalizes with junctophilin (JPH) 3 and 4 proteins that tether the plasma membrane to the endoplasmic reticulum. JPH3 and JPH4 shRNAs dissociated a Cav1.3-RyR2-KCa3.1 complex and reduced the IsAHP. Infusing JPH3 and JPH4 antibodies into CA1 cells reduced IsAHP and spike accommodation. These data indicate that JPH3 and JPH4 proteins maintain a Cav1-RyR2-KCa3.1 complex that allows two calcium sources to act in tandem to define the activation properties of KCa3.1 channels and the IsAHP. : Sahu et al. establish that junctophilin proteins maintain a triprotein complex that assembles a voltage-gated plasma membrane calcium channel and endoplasmic reticular ryanodine receptors with a calcium-gated potassium channel to generate the long-duration slow afterhyperpolarization that regulates spike output in hippocampal pyramidal cells. Keywords: CaV1.3, Cav1.2, KCa3.1, ryanodine receptor, RyR2, junctophilin, sAHP, hippocampus, dSTORM, FRET
    Keywords Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2019-08-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: FMRP(1–297)-tat restores ion channel and synaptic function in a model of Fragile X syndrome

    Xiaoqin Zhan / Hadhimulya Asmara / Ning Cheng / Giriraj Sahu / Eduardo Sanchez / Fang-Xiong Zhang / Gerald W. Zamponi / Jong M. Rho / Ray W. Turner

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 16

    Abstract: Fragile X Mental Retardation Protein regulates synaptic plasticity and its loss results in Fragile X Syndrome. Here, the authors show that the FMRP(1-297)-tat peptide can permeate the BBB, restore protein translation and mossy fiber LTP, and reduce ... ...

    Abstract Fragile X Mental Retardation Protein regulates synaptic plasticity and its loss results in Fragile X Syndrome. Here, the authors show that the FMRP(1-297)-tat peptide can permeate the BBB, restore protein translation and mossy fiber LTP, and reduce elevated levels of activity in Fmr1 KO mice.
    Keywords Science ; Q
    Language English
    Publishing date 2020-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: FMRP(1–297)-tat restores ion channel and synaptic function in a model of Fragile X syndrome

    Xiaoqin Zhan / Hadhimulya Asmara / Ning Cheng / Giriraj Sahu / Eduardo Sanchez / Fang-Xiong Zhang / Gerald W. Zamponi / Jong M. Rho / Ray W. Turner

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 16

    Abstract: Fragile X Mental Retardation Protein regulates synaptic plasticity and its loss results in Fragile X Syndrome. Here, the authors show that the FMRP(1-297)-tat peptide can permeate the BBB, restore protein translation and mossy fiber LTP, and reduce ... ...

    Abstract Fragile X Mental Retardation Protein regulates synaptic plasticity and its loss results in Fragile X Syndrome. Here, the authors show that the FMRP(1-297)-tat peptide can permeate the BBB, restore protein translation and mossy fiber LTP, and reduce elevated levels of activity in Fmr1 KO mice.
    Keywords Science ; Q
    Language English
    Publishing date 2020-06-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Limiting RyR2 Open Time Prevents Alzheimer’s Disease-Related Neuronal Hyperactivity and Memory Loss but Not β-Amyloid Accumulation

    Jinjing Yao / Bo Sun / Adam Institoris / Xiaoqin Zhan / Wenting Guo / Zhenpeng Song / Yajing Liu / Florian Hiess / Andrew K.J. Boyce / Mingke Ni / Ruiwu Wang / Henk ter Keurs / Thomas G. Back / Michael Fill / Roger J. Thompson / Ray W. Turner / Grant R. Gordon / S.R. Wayne Chen

    Cell Reports, Vol 32, Iss 12, Pp 108169- (2020)

    2020  

    Abstract: Summary: Neuronal hyperactivity is an early primary dysfunction in Alzheimer’s disease (AD) in humans and animal models, but effective neuronal hyperactivity-directed anti-AD therapeutic agents are lacking. Here we define a previously unknown mode of ... ...

    Abstract Summary: Neuronal hyperactivity is an early primary dysfunction in Alzheimer’s disease (AD) in humans and animal models, but effective neuronal hyperactivity-directed anti-AD therapeutic agents are lacking. Here we define a previously unknown mode of ryanodine receptor 2 (RyR2) control of neuronal hyperactivity and AD progression. We show that a single RyR2 point mutation, E4872Q, which reduces RyR2 open time, prevents hyperexcitability, hyperactivity, memory impairment, neuronal cell death, and dendritic spine loss in a severe early-onset AD mouse model (5xFAD). The RyR2-E4872Q mutation upregulates hippocampal CA1-pyramidal cell A-type K+ current, a well-known neuronal excitability control that is downregulated in AD. Pharmacologically limiting RyR2 open time with the R-carvedilol enantiomer (but not racemic carvedilol) prevents and rescues neuronal hyperactivity, memory impairment, and neuron loss even in late stages of AD. These AD-related deficits are prevented even with continued β-amyloid accumulation. Thus, limiting RyR2 open time may be a hyperactivity-directed, non-β-amyloid-targeted anti-AD strategy.
    Keywords Alzheimer’s disease ; β-amyloid deposition ; learning and memory ; hippocampal CA1 pyramidal neurons ; neuronal hyperactivity ; neuronal excitability ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Low voltage activation of KCa1.1 current by Cav3-KCa1.1 complexes.

    Renata Rehak / Theodore M Bartoletti / Jordan D T Engbers / Geza Berecki / Ray W Turner / Gerald W Zamponi

    PLoS ONE, Vol 8, Iss 4, p e

    2013  Volume 61844

    Abstract: Calcium-activated potassium channels of the KCa1.1 class are known to regulate repolarization of action potential discharge through a molecular association with high voltage-activated calcium channels. The current study examined the potential for low ... ...

    Abstract Calcium-activated potassium channels of the KCa1.1 class are known to regulate repolarization of action potential discharge through a molecular association with high voltage-activated calcium channels. The current study examined the potential for low voltage-activated Cav3 (T-type) calcium channels to interact with KCa1.1 when expressed in tsA-201 cells and in rat medial vestibular neurons (MVN) in vitro. Expression of the channel α-subunits alone in tsA-201 cells was sufficient to enable Cav3 activation of KCa1.1 current. Cav3 calcium influx induced a 50 mV negative shift in KCa1.1 voltage for activation, an interaction that was blocked by Cav3 or KCa1.1 channel blockers, or high internal EGTA. Cav3 and KCa1.1 channels coimmunoprecipitated from lysates of either tsA-201 cells or rat brain, with Cav3 channels associating with the transmembrane S0 segment of the KCa1.1 N-terminus. KCa1.1 channel activation was closely aligned with Cav3 calcium conductance in that KCa1.1 current shared the same low voltage dependence of Cav3 activation, and was blocked by voltage-dependent inactivation of Cav3 channels or by coexpressing a non calcium-conducting Cav3 channel pore mutant. The Cav3-KCa1.1 interaction was found to function highly effectively in a subset of MVN neurons by activating near -50 mV to contribute to spike repolarization and gain of firing. Modelling data indicate that multiple neighboring Cav3-KCa1.1 complexes must act cooperatively to raise calcium to sufficiently high levels to permit KCa1.1 activation. Together the results identify a novel Cav3-KCa1.1 signaling complex where Cav3-mediated calcium entry enables KCa1.1 activation over a wide range of membrane potentials according to the unique voltage profile of Cav3 calcium channels, greatly extending the roles for KCa1.1 potassium channels in controlling membrane excitability.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572 ; 571
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: IKCa Channels Are a Critical Determinant of the Slow AHP in CA1 Pyramidal Neurons

    Brian King / Arsalan P. Rizwan / Hadhimulya Asmara / Norman C. Heath / Jordan D.T. Engbers / Steven Dykstra / Theodore M. Bartoletti / Shahid Hameed / Gerald W. Zamponi / Ray W. Turner

    Cell Reports, Vol 11, Iss 2, Pp 175-

    2015  Volume 182

    Abstract: Control over the frequency and pattern of neuronal spike discharge depends on Ca2+-gated K+ channels that reduce cell excitability by hyperpolarizing the membrane potential. The Ca2+-dependent slow afterhyperpolarization (sAHP) is one of the most ... ...

    Abstract Control over the frequency and pattern of neuronal spike discharge depends on Ca2+-gated K+ channels that reduce cell excitability by hyperpolarizing the membrane potential. The Ca2+-dependent slow afterhyperpolarization (sAHP) is one of the most prominent inhibitory responses in the brain, with sAHP amplitude linked to a host of circuit and behavioral functions, yet the channel that underlies the sAHP has defied identification for decades. Here, we show that intermediate-conductance Ca2+-dependent K+ (IKCa) channels underlie the sAHP generated by trains of synaptic input or postsynaptic stimuli in CA1 hippocampal pyramidal cells. These findings are significant in providing a molecular identity for the sAHP of central neurons that will identify pharmacological tools capable of potentially modifying the several behavioral or disease states associated with the sAHP.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2015-04-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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