Disrupted Ontogeny of Cortical GABA Neurons in Schizophrenia

精神分裂症皮质 GABA 神经元的个体发育受到破坏

基本信息

  • 批准号:
    8629984
  • 负责人:
  • 金额:
    $ 46.29万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-12-01 至 2018-11-30
  • 项目状态:
    已结题

项目摘要

Project Summary Cognitive impairments in schizophrenia (SZ) have been linked to dysfunction of inhibitory prefrontal cortex (PFC) circuitry, including parvalbumin (PV) and somatostatin (SST) neurons. We recently found that disturbances in PFC PV&SST neurons are most prominent in a subset (~50%) of SZ subjects identified as a "low GABA marker" (LGM) molecular phenotype. The etiopathogenesis of PV&SST neuron dysfunction in the LGM SZ subjects may be influenced by genetic liabilities and/or environmental insults that affect neuronal ontogeny. In humans, embryonic PV&SST neurons express developmental regulators (e.g., Lhx6) and cytokine receptors that regulate their specification and migration. We recently found deficits in PFC Lhx6 mRNA levels that were most prominent in the LGM SZ subjects, suggesting that low Lhx6 levels may impair PV&SST neuron development in SZ. In addition, disturbances in the fetal environment, such as elevated cytokine levels due to maternal immune activation (MIA), increase risk for SZ and lower cortical PV levels. These data suggest that prenatal exposure to altered cytokine levels due to MIA may disrupt the development of cytokine receptor-expressing neurons. Since loss of Lhx6 induces deficits in cytokine receptors and MIA lowers Lhx6 levels, the combination of Lhx6 deficits and MIA may severely disrupt PV&SST neuron development. Therefore, we hypothesize that disturbances in PV&SST neurons in SZ subjects with the LGM phenotype reflect the long-lasting consequences of prenatal insults that are fetal (i.e. deficits in developmental regulators such as Lhx6) and/or maternal (i.e. immune activation) in origin. Testing this central hypothesis requires a translational, cross-species approach. In Aim 1 we will use tissue and cellular measures of mRNA levels of developmental factors and cytokine receptors critical for PFC PV&SST neuron ontogeny and other immune markers in the PFC of SZ and healthy subjects. We hypothesize that SZ subjects with the LGM phenotype show a pattern of low mRNA levels for developmental factors and high mRNA levels for immune markers relative to other SZ and healthy subjects. SZ and bipolar disorder (BP) share features including genetic risk, psychosis, cognitive impairments, and low PFC PV and GAD67 mRNA levels. In Aim 2 we will investigate whether a shared pathogenetic mechanism may disrupt PV&SST neuron ontogeny by conducting mRNA studies similar to Aim 1 in BP subjects. We hypothesize that the LGM phenotype and deficits in developmental factors are also present in a subset of BP subjects, but at a lower frequency than SZ. Finally, in Aim 3 we will investigate a potential pathogenetic mechanism that may lead to the LGM phenotype by administering poly I:C which induces cytokine response to pregnant wild-type mice (Lhx6+/- male progenitors) and conducting studies of PFC PV&SST neuron developmental regulators and neurophysiology measures in offspring. We hypothesize that deficits in Lhx6 or MIA independently, and their interaction more severely, leads to deficits in adult PV&SST neurons akin to those seen in the LGM phenotype.
项目摘要 精神分裂症患者的认知障碍与抑制性前额叶皮质功能障碍有关 (PFC)回路,包括小白蛋白(PV)和生长抑素(SST)神经元。我们最近发现, PFC、PV和SST神经元的干扰在SZ受试者中最突出(~50%),被确定为 “低GABA标记”(LGM)分子表型。大鼠PV和SST神经元功能障碍的发病机制 LGM SZ受试者可能会受到遗传缺陷和/或影响神经元的环境侮辱的影响 个体发育学。在人类中,胚胎PV和SST神经元表达发育调节因子(例如Lhx6)和 调节它们的规格和迁移的细胞因子受体。我们最近发现PFC Lhx6存在缺陷 在LGM SZ受试者中最显著的mRNA水平,表明低Lhx6水平可能会损害 深圳地区PV和SST神经元的发育。此外,胎儿环境的紊乱,如升高 母体免疫激活(MIA)导致的细胞因子水平增加了SZ的风险,降低了皮质PV水平。 这些数据表明,产前暴露于MIA引起的细胞因子水平变化可能会扰乱发育 表达细胞因子受体的神经元。由于Lhx6的丢失导致细胞因子受体和MIA的缺陷 降低Lhx6水平,Lhx6缺陷和MIA的结合可能严重扰乱PV和SST神经元 发展。因此,我们假设SZ受试者的PV和SST神经元的干扰 LGM表型反映了胎儿性产前侮辱的长期后果(即 发育调节因子,如Lhx6)和/或母体(即免疫激活)。测试这一点 中心假说需要一种翻译的、跨物种的方法。在目标1中,我们将使用组织和细胞 PFC PV和SST神经元关键发育因子和细胞因子受体mRNA水平的测定 SZ和健康人PFC的个体发育和其他免疫标志物。我们假设深圳的受试者 LGM表型表现为发育因子低表达,高表达 免疫标记物水平相对于其他SZ和健康受试者。深圳与双相情感障碍(BP)相同 特征包括遗传风险、精神病、认知障碍以及低水平的PFC PV和GAD67 mRNA水平。 在目标2中,我们将研究共同的致病机制是否可能扰乱PV和SST神经元的个体发育 通过在BP受试者中进行类似于目标1的mRNA研究。我们假设lgm表型和 发育因素缺陷也存在于一部分BP受试者中,但频率较低 而不是SZ。最后,在目标3中,我们将研究可能导致LGM的潜在致病机制 通过给予Poly I:C诱导怀孕野生型小鼠(Lhx6+/-雄性)的表型 祖细胞),并进行PFC、PV和SST神经元发育调节和神经生理学的研究 在后代身上进行测量。我们假设Lhx6或MIA中的缺陷独立存在,以及它们之间的相互作用 更严重的是,导致成年PV和SST神经元的缺陷,类似于LGM表型。

项目成果

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DAVID W VOLK其他文献

DAVID W VOLK的其他文献

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{{ truncateString('DAVID W VOLK', 18)}}的其他基金

Microglial Phagocytosis of Dendritic Spines in Veterans with Schizophrenia
精神分裂症退伍军人的小胶质细胞吞噬树突棘
  • 批准号:
    9884687
  • 财政年份:
    2020
  • 资助金额:
    $ 46.29万
  • 项目类别:
Microglial Phagocytosis of Dendritic Spines in Veterans with Schizophrenia
精神分裂症退伍军人的小胶质细胞吞噬树突棘
  • 批准号:
    10455417
  • 财政年份:
    2020
  • 资助金额:
    $ 46.29万
  • 项目类别:
Microglial Phagocytosis of Dendritic Spines in Veterans with Schizophrenia
精神分裂症退伍军人的小胶质细胞吞噬树突棘
  • 批准号:
    10619593
  • 财政年份:
    2020
  • 资助金额:
    $ 46.29万
  • 项目类别:
Disrupted Ontogeny of Cortical GABA Neurons in Schizophrenia
精神分裂症皮质 GABA 神经元的个体发育受到破坏
  • 批准号:
    9186566
  • 财政年份:
    2013
  • 资助金额:
    $ 46.29万
  • 项目类别:
Schizophrenia and Endocannabinoid Effects on Inhibitory Circuitry
精神分裂症和内源性大麻素对抑制回路的影响
  • 批准号:
    8393503
  • 财政年份:
    2009
  • 资助金额:
    $ 46.29万
  • 项目类别:
Schizophrenia and Endocannabinoid Effects on Inhibitory Circuitry
精神分裂症和内源性大麻素对抑制回路的影响
  • 批准号:
    8204936
  • 财政年份:
    2009
  • 资助金额:
    $ 46.29万
  • 项目类别:
Schizophrenia and Endocannabinoid Effects on Inhibitory Circuitry
精神分裂症和内源性大麻素对抑制回路的影响
  • 批准号:
    7998198
  • 财政年份:
    2009
  • 资助金额:
    $ 46.29万
  • 项目类别:
Schizophrenia and Endocannabinoid Effects on Inhibitory Circuitry
精神分裂症和内源性大麻素对抑制回路的影响
  • 批准号:
    7662628
  • 财政年份:
    2009
  • 资助金额:
    $ 46.29万
  • 项目类别:
Schizophrenia and Endocannabinoid Effects on Inhibitory Circuitry
精神分裂症和内源性大麻素对抑制回路的影响
  • 批准号:
    7798063
  • 财政年份:
    2009
  • 资助金额:
    $ 46.29万
  • 项目类别:
Altered Inhibitory Prefrontal Circuitry in Schizophrenia
精神分裂症抑制性前额叶回路的改变
  • 批准号:
    6607356
  • 财政年份:
    2002
  • 资助金额:
    $ 46.29万
  • 项目类别:

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