Neuroligin-1 as a new molecular substrate of the phosphatase STEP, and its involvement in homeostatic synaptic plasticity and memory function

Neuroligin-1作为磷酸酶STEP的新分子底物及其参与稳态突触可塑性和记忆功能

基本信息

  • 批准号:
    RGPIN-2016-05504
  • 负责人:
  • 金额:
    $ 2.26万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2019
  • 资助国家:
    加拿大
  • 起止时间:
    2019-01-01 至 2020-12-31
  • 项目状态:
    已结题

项目摘要

Understanding the molecular mechanisms underlying synaptic plasticity is a fundamental goal in neurobiology. Alteration in synaptic strength underlies memory formation in the neuronal network circuitry, whereas homeostatic synaptic plasticity maintains neuronal changes within physiological limit. We know that the glutamatergic N-methyl-D-aspartate receptor (NMDAR) and -amino-3-hydroxyle-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) are both critically involved in both forms of synaptic plasticity. However, the molecular mechanisms controlling these receptors during synaptic plasticity still need to be fully established. A key modulator of both receptors is the tyrosine phosphatase STEP (STriatal Enriched Phosphatase) that counteract synaptic strengthening by dephosphorylating and promoting internalization of the NMDAR and AMPAR. Although we know that STEP is involved in homeostatic plasticity, the molecular mechanisms sustaining its action remain to be established. Moreover, we still ignore how STEP interacts with the AMPAR, which prompts us to uncover novel molecules that might represent the missing link between STEP and AMPAR.*** The protein Neuroligin-1 (NLG1) is an interesting candidate regulated by STEP for several reasons. Like STEP, NLG1 is located at the post-synaptic membrane of glutamate synapses, and is involved in the formation and stabilization of synaptic connections by activating the NMDAR and AMPAR. Although we know that the phosphorylation state of NLG1at a unique tyrosine (Y782) induced synapse formation and stabilization, the identity of the proteins that regulate Y782 is still unknown. The central hypothesis of this program is that NLG1 is a new molecular component of the STEP signaling cascade involved in the establishment of homeostatic synaptic plasticity and memory formation. We will test this hypothesis according to three specific objectives:***Objective 1: Uncover the protein interaction of STEP and NLG1 during homeostatic synaptic plasticity in vitro.***Objective 2: Demonstrate that dephosphorylation of NLG1 by STEP alters synaptic plasticity underlying memory formation in vitro.***Objective 3: Evaluate if STEP and NLG1 binding affects homeostatic synaptic plasticity and memory formation in vivo.*** The long-term objective of this research program is to understand the fundamental molecular mechanisms of synaptic plasticity. The benefits of this research are numerous and have a strong potential to uncover key signaling pathways involved in homeostatic synaptic plasticity. A clearer comprehension of the molecular mechanisms that govern synaptic plasticity will bring new insights on how the brain forms and stores novel information.********
了解突触可塑性的分子机制是神经生物学的一个基本目标。突触强度的改变是神经元网络回路中记忆形成的基础,而稳态突触可塑性将神经元的变化维持在生理限度内。我们知道,N-甲基-D-天冬氨酸受体(NMDAR)和β-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体(AMPAR)都参与了这两种形式的突触可塑性。然而,在突触可塑性过程中控制这些受体的分子机制仍然需要完全建立。这两种受体的关键调节剂是酪氨酸磷酸酶STEP(STriatal Enriched Phosphatase),其通过NMDAR和AMPAR的去磷酸化和促进内化来抵消突触强化。虽然我们知道STEP参与稳态可塑性,但维持其作用的分子机制仍有待建立。此外,我们仍然忽略了STEP如何与AMPAR相互作用,这促使我们发现可能代表STEP和AMPAR之间缺失环节的新分子。 神经连接素-1(NLG1)蛋白是STEP调控的一个有趣的候选者,有几个原因。与STEP一样,NLG1位于谷氨酸突触的突触后膜,并通过激活NMDAR和AMPAR参与突触连接的形成和稳定。虽然我们知道NLG 1在一个独特的酪氨酸(Y782)的磷酸化状态诱导突触的形成和稳定,但调控Y782的蛋白质的身份仍然未知。该计划的中心假设是NLG1是STEP信号级联的新分子组分,参与稳态突触可塑性和记忆形成的建立。我们将根据三个具体目标来检验这一假设:* 目标1:揭示STEP和NLG 1在体外稳态突触可塑性过程中的蛋白质相互作用。目的2:证明STEP对NLG 1的去磷酸化改变了体外记忆形成的突触可塑性。目的3:评估STEP和NLG 1结合是否影响体内稳态突触可塑性和记忆形成。 这项研究计划的长期目标是了解突触可塑性的基本分子机制。这项研究的好处是多方面的,并有很大的潜力,发现关键的信号通路参与稳态突触可塑性。对控制突触可塑性的分子机制有了更清楚的理解,将为大脑如何形成和储存新信息带来新的见解。

项目成果

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Brouillette, Jonathan其他文献

Tau hyperphosphorylation induced by the anesthetic agent ketamine/xylazine involved the calmodulin-dependent protein kinase II
  • DOI:
    10.1096/fj.201902135r
  • 发表时间:
    2019-12-26
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Hector, Audrey;McAnulty, Christina;Brouillette, Jonathan
  • 通讯作者:
    Brouillette, Jonathan
Tau Phosphorylation and Sevoflurane Anesthesia An Association to Postoperative Cognitive Impairment
  • DOI:
    10.1097/aln.0b013e31824be8c7
  • 发表时间:
    2012-04-01
  • 期刊:
  • 影响因子:
    8.8
  • 作者:
    Le Freche, Helene;Brouillette, Jonathan;Buee, Luc
  • 通讯作者:
    Buee, Luc
The common environmental pollutant dioxin-induced memory deficits by altering estrogen pathways and a major route of retinol transport involving transthyretin
  • DOI:
    10.1016/j.neuro.2007.12.005
  • 发表时间:
    2008-03-01
  • 期刊:
  • 影响因子:
    3.4
  • 作者:
    Brouillette, Jonathan;Quirion, Remi
  • 通讯作者:
    Quirion, Remi
Neurotoxicity and Memory Deficits Induced by Soluble Low-Molecular-Weight Amyloid-β1-42 Oligomers Are Revealed In Vivo by Using a Novel Animal Model
  • DOI:
    10.1523/jneurosci.5901-11.2012
  • 发表时间:
    2012-06-06
  • 期刊:
  • 影响因子:
    5.3
  • 作者:
    Brouillette, Jonathan;Caillierez, Raphaelle;Buee, Luc
  • 通讯作者:
    Buee, Luc
Hippocampal gene expression profiling reveals the possible involvement of Homer1 and GABAB receptors in scopolamine-induced amnesia
  • DOI:
    10.1111/j.1471-4159.2007.04666.x
  • 发表时间:
    2007-09-01
  • 期刊:
  • 影响因子:
    4.7
  • 作者:
    Brouillette, Jonathan;Young, Deborah;Quirion, Remi
  • 通讯作者:
    Quirion, Remi

Brouillette, Jonathan的其他文献

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{{ truncateString('Brouillette, Jonathan', 18)}}的其他基金

Neuroligin-1 as a new molecular substrate of the phosphatase STEP, and its involvement in homeostatic synaptic plasticity and memory function
Neuroligin-1作为磷酸酶STEP的新分子底物及其参与稳态突触可塑性和记忆功能
  • 批准号:
    RGPIN-2016-05504
  • 财政年份:
    2021
  • 资助金额:
    $ 2.26万
  • 项目类别:
    Discovery Grants Program - Individual
Neuroligin-1 as a new molecular substrate of the phosphatase STEP, and its involvement in homeostatic synaptic plasticity and memory function
Neuroligin-1作为磷酸酶STEP的新分子底物及其参与稳态突触可塑性和记忆功能
  • 批准号:
    RGPIN-2016-05504
  • 财政年份:
    2020
  • 资助金额:
    $ 2.26万
  • 项目类别:
    Discovery Grants Program - Individual
Neuroligin-1 as a new molecular substrate of the phosphatase STEP, and its involvement in homeostatic synaptic plasticity and memory function
Neuroligin-1作为磷酸酶STEP的新分子底物及其参与稳态突触可塑性和记忆功能
  • 批准号:
    RGPIN-2016-05504
  • 财政年份:
    2018
  • 资助金额:
    $ 2.26万
  • 项目类别:
    Discovery Grants Program - Individual
Neuroligin-1 as a new molecular substrate of the phosphatase STEP, and its involvement in homeostatic synaptic plasticity and memory function
Neuroligin-1作为磷酸酶STEP的新分子底物及其参与稳态突触可塑性和记忆功能
  • 批准号:
    RGPIN-2016-05504
  • 财政年份:
    2017
  • 资助金额:
    $ 2.26万
  • 项目类别:
    Discovery Grants Program - Individual
Neuroligin-1 as a new molecular substrate of the phosphatase STEP, and its involvement in homeostatic synaptic plasticity and memory function
Neuroligin-1作为磷酸酶STEP的新分子底物及其参与稳态突触可塑性和记忆功能
  • 批准号:
    RGPIN-2016-05504
  • 财政年份:
    2016
  • 资助金额:
    $ 2.26万
  • 项目类别:
    Discovery Grants Program - Individual

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Neuroligin-1 as a new molecular substrate of the phosphatase STEP, and its involvement in homeostatic synaptic plasticity and memory function
Neuroligin-1作为磷酸酶STEP的新分子底物及其参与稳态突触可塑性和记忆功能
  • 批准号:
    RGPIN-2016-05504
  • 财政年份:
    2021
  • 资助金额:
    $ 2.26万
  • 项目类别:
    Discovery Grants Program - Individual
Neuroligin-1 as a new molecular substrate of the phosphatase STEP, and its involvement in homeostatic synaptic plasticity and memory function
Neuroligin-1作为磷酸酶STEP的新分子底物及其参与稳态突触可塑性和记忆功能
  • 批准号:
    RGPIN-2016-05504
  • 财政年份:
    2020
  • 资助金额:
    $ 2.26万
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    Discovery Grants Program - Individual
The role of Neuroligin 2 in the regulation of GABAergic interneuron activity and cortical inhibition
Neuroligin 2 在 GABA 能中间神经元活性和皮质抑制调节中的作用
  • 批准号:
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The role of Neuroligin 2 in the regulation of GABAergic interneuron activity and cortical inhibition
Neuroligin 2 在 GABA 能中间神经元活性和皮质抑制调节中的作用
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Neuroligin 2 在 GABA 能中间神经元活性和皮质抑制调节中的作用
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  • 财政年份:
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Neuroligin-1 as a new molecular substrate of the phosphatase STEP, and its involvement in homeostatic synaptic plasticity and memory function
Neuroligin-1作为磷酸酶STEP的新分子底物及其参与稳态突触可塑性和记忆功能
  • 批准号:
    RGPIN-2016-05504
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    $ 2.26万
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    Discovery Grants Program - Individual
Neuroligin-1 as a new molecular substrate of the phosphatase STEP, and its involvement in homeostatic synaptic plasticity and memory function
Neuroligin-1作为磷酸酶STEP的新分子底物及其参与稳态突触可塑性和记忆功能
  • 批准号:
    RGPIN-2016-05504
  • 财政年份:
    2017
  • 资助金额:
    $ 2.26万
  • 项目类别:
    Discovery Grants Program - Individual
Neuroligin-1 as a new molecular substrate of the phosphatase STEP, and its involvement in homeostatic synaptic plasticity and memory function
Neuroligin-1作为磷酸酶STEP的新分子底物及其参与稳态突触可塑性和记忆功能
  • 批准号:
    RGPIN-2016-05504
  • 财政年份:
    2016
  • 资助金额:
    $ 2.26万
  • 项目类别:
    Discovery Grants Program - Individual
Variation in Neuroligin Concentration and Presynaptic Functional Development
Neuroligin 浓度的变化和突触前功能发育
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Variation in Neuroligin Concentration and Presynaptic Functional Development
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