Consequences of In Vivo Neocortical GAD67 Downregulation

体内新皮质 GAD67 下调的后果

基本信息

  • 批准号:
    8264218
  • 负责人:
  • 金额:
    $ 34.19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-07-01 至 2014-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Glutamic acid decarboxylase 67kDa (GAD67) transcript reduction in the postmortem prefrontal cortex is the most robust and consistently replicated finding across different cohorts of subjects with schizophrenia. This critical, brain-specific GABA synthesis enzyme is shows expression deficit in distinct interneuronal populations of the human cortex. As a result, we expect that a directed cortical downregulation of GAD67 in these distinct interneuronal subphenotypes will 1) mimic the human postmortem findings in schizophrenia 2) have distinct consequences on cortical functioning and 3) lead to a better understanding of cortical inhibition. In this proposal, we hypothesize that in vivo downregulation of GAD67 in SST, NPY, CCK and PARV-containing cortical interneurons will result in distinct anatomical, neurochemical, molecular and behavioral changes that will share common features with human schizophrenia. To test our central hypothesis we propose 4 specific Aims which will focus on the generation and characterization of four transgenic mouse lines. In Aim 1 we will generate four distinct, GFP-labeled, GAD67 hypomorphic mice under the control of SST, NPY, CCK and PARV promoters. We will achieve this using a mouse bacterial artificial chromosome (BAC) containing SST, NPY, CCK and PARV promoter/enhancer regions modified to express both GFP and an intron-encoded microRNA (miRNA) specific to GAD67. In Aim 2 we will perform an anatomical/neurochemical assessment of the newly generated transgenic mice strains. We will assess each mouse line by gross anatomical measurements, general microanatomy and neurochemical methods. Aim 3 will focus on behavioral assessment of the four GAD67 knockdown mice strains. Beyond the basic behavioral characterization of the mice (neurological exam and sensorymotor assessments) we will assess prepulse inhibition, spatial working memory and social behaviors. Aim 4 will establish the neocortical gene expression changes that are shared between GAD67 KO mice and expression alterations in the PFC of schizophrenia. Downregulation of GAD67 transcripts in specific interneuronal subpopulations will likely lead to expression changes in both interneurons and pyramidal cells, and we believe that some of these expression changes will mimic the expression changes seen in human postmortem brain of subjects with schizophrenia. To test this, for each of the knockdown animals showing a behavioral/anatomical phenotype, we will the expression of genes known to be altered in human schizophrenia (e.g. SYN2, RGS4, MOG, SST, NPY, GAD67, HSP70, AMPA etc). The first transgenic mouse line, with GAD67 downregulation in the PARV+ interneuronal subpopulation has been successfully generated and awaits characterization. PUBLIC HEALTH RELEVANCE: Neocortical interneuronal downregulation of GAD67 expression is one of the most consistently replicated findings of schizophrenia. The proposed studies will focus on the consequences of in vivo downregulation of GAD67 in specific cortical interneuronal subpopulations, and relate them to the postmortem findings in the brains of subjects with schizophrenia.
描述(由申请方提供):在精神分裂症受试者的不同队列中,死后前额叶皮层中谷氨酸脱羧酶67 kDa(GAD 67)转录物减少是最稳健和一致重复的发现。这种关键的脑特异性GABA合成酶在人类皮层的不同神经元间群体中显示出表达缺陷。因此,我们预期在这些不同的神经元间亚表型中GAD 67的定向皮质下调将1)模拟精神分裂症中的人类尸检结果2)对皮质功能具有不同的后果3)导致更好地理解皮质抑制。在这个建议中,我们假设,在SST,NPY,CCK和PARV含有皮质中间神经元的GAD 67在体内下调将导致不同的解剖,神经化学,分子和行为的变化,将共享与人类精神分裂症的共同特征。为了检验我们的中心假设,我们提出了4个具体的目标,重点是四个转基因小鼠系的产生和表征。在目标1中,我们将产生四个不同的,GFP标记的,GAD 67亚型小鼠的SST,NPY,CCK和PARV启动子的控制下。我们将使用小鼠细菌人工染色体(BAC)来实现这一点,所述小鼠细菌人工染色体(BAC)含有SST、NPY、CCK和PARV启动子/增强子区域,所述启动子/增强子区域经修饰以表达GFP和对GAD 67特异性的内含子编码的微小RNA(miRNA)。在目标2中,我们将对新产生的转基因小鼠品系进行解剖学/神经化学评估。我们将通过大体解剖测量、一般显微解剖和神经化学方法评估每个小鼠品系。目的3将集中于四种GAD 67敲低小鼠品系的行为评估。除了小鼠的基本行为特征(神经学检查和感觉运动评估),我们还将评估前脉冲抑制、空间工作记忆和社会行为。目的4建立GAD 67基因敲除小鼠新皮层基因表达的改变和精神分裂症PFC基因表达的改变。GAD 67转录在特定的interneuronal亚群的下调可能会导致表达的变化,在interneurons和锥体细胞,我们相信,这些表达的变化将模仿在人类死后的精神分裂症患者的大脑中看到的表达变化。为了测试这一点,对于显示出行为/解剖学表型的每个敲除动物,我们将检测已知在人精神分裂症中改变的基因(例如SYN2、RGS4、MOG、SST、NPY、GAD 67、HSP 70、AMPA等)的表达。第一个转基因小鼠系,GAD 67下调PARV+神经元间亚群已成功产生,并等待表征。公共卫生相关性:新皮质神经元间GAD 67表达下调是精神分裂症最一致的重复结果之一。拟议的研究将集中在特定的皮质神经元亚群中GAD 67的体内下调的后果,并将其与精神分裂症受试者大脑中的尸检结果联系起来。

项目成果

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Karoly Mirnics其他文献

Karoly Mirnics的其他文献

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{{ truncateString('Karoly Mirnics', 18)}}的其他基金

Vulnerability of DHCR7+/- mutation carriers to aripiprazole and trazodone treatment
DHCR7/-突变携带者对阿立哌唑和曲唑酮治疗的脆弱性
  • 批准号:
    9312958
  • 财政年份:
    2017
  • 资助金额:
    $ 34.19万
  • 项目类别:
CORE B: Basic Neuroscience Services
核心 B:基础神经科学服务
  • 批准号:
    7758947
  • 财政年份:
    2009
  • 资助金额:
    $ 34.19万
  • 项目类别:
Neuroimmune Changes in Schizophrenia
精神分裂症的神经免疫变化
  • 批准号:
    7570616
  • 财政年份:
    2007
  • 资助金额:
    $ 34.19万
  • 项目类别:
MOLECULAR PROFILE OF LAMINA-SPECIFIC ALTERATIONS IN THE DLPFC IN SCHIZOPHRENIA
精神分裂症 DLPFC 层特异性改变的分子谱
  • 批准号:
    7553453
  • 财政年份:
    2007
  • 资助金额:
    $ 34.19万
  • 项目类别:
Neuroimmune Changes in Schizophrenia
精神分裂症的神经免疫变化
  • 批准号:
    7775052
  • 财政年份:
    2007
  • 资助金额:
    $ 34.19万
  • 项目类别:
Neuroimmune Changes in Schizophrenia
精神分裂症的神经免疫变化
  • 批准号:
    7188736
  • 财政年份:
    2007
  • 资助金额:
    $ 34.19万
  • 项目类别:
Neuroimmune Changes in Schizophrenia
精神分裂症的神经免疫变化
  • 批准号:
    8034743
  • 财政年份:
    2007
  • 资助金额:
    $ 34.19万
  • 项目类别:
Uncovering complex expression patterns in schizophrenia
揭示精神分裂症的复杂表达模式
  • 批准号:
    7302969
  • 财政年份:
    2004
  • 资助金额:
    $ 34.19万
  • 项目类别:
Uncovering complex expression patterns in schizophrenia
揭示精神分裂症的复杂表达模式
  • 批准号:
    7215620
  • 财政年份:
    2004
  • 资助金额:
    $ 34.19万
  • 项目类别:
Uncovering complex expression patterns in schizophrenia
揭示精神分裂症的复杂表达模式
  • 批准号:
    6762965
  • 财政年份:
    2004
  • 资助金额:
    $ 34.19万
  • 项目类别:

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