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
• 负责人: DAVID W VOLK
• 金额: $ 42.8万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9186566
• 关键词: Adult; Affect; Age; Antipsychotic Agents; Autopsy; Bipolar Disorder; Brain; CXCR4 gene; Clinical; Cognitive; Cytokine Receptors; Data; Development; Embryo; Employment; Environment; ErbB4 gene; Exposure to; Frequencies; Functional disorder; GABA Agents; GAD67 enzyme; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic screening method; Growth; Human; Image; Immune; Immunofluorescence Microscopy; Immunologic Markers; Impaired cognition; Impairment; Infection; Knock-out; Lead; Link; Measures; Mental disorders; Messenger RNA; Molecular; Monkeys; Mus; Nature; Neurons; Parvalbumins; Patients; Pattern; Phenotype; Poly I-C; Prefrontal Cortex; Prenatal care; Presynaptic Terminals; Prevention strategy; Psychotic Disorders; Reporting; Risk; Saline; Schizophrenia; Somatostatin; Testing; Tissues; Wild Type Mouse; cytokine; experience; fetal; gamma-Aminobutyric Acid; immune activation; male; migration; molecular marker; molecular phenotype; mouse model; neuron development; neurophysiology; novel; novel diagnostics; novel strategies; offspring; personalized medicine; phenotypic biomarker; pregnant; prenatal; prenatal exposure; prepulse inhibition; progenitor; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：精神分裂症（SZ）的认知障碍与抑制性前额叶皮层（PFC）电路的功能障碍有关，包括小清蛋白（PV）和生长抑素（SST）神经元。我们最近发现，PFC PV 和 SST 神经元的紊乱在被确定为“低 GABA 标记”(LGM) 分子表型的 SZ 受试者亚群 (~50%) 中最为突出。 LGM SZ 受试者中 PV 和 SST 神经元功能障碍的发病机制可能受到影响神经元个体发育的遗传倾向和/或环境损伤的影响。在人类中，胚胎 PV 和 SST 神经元表达发育调节因子（例如 Lhx6）和调节其规范和迁移的细胞因子受体。我们最近发现 PFC Lhx6 mRNA 水平的缺陷在 LGM SZ 受试者中最为突出，表明低 Lhx6 水平可能会损害 SZ 中的 PV 和 SST 神经元发育。此外，胎儿环境的干扰，例如母体免疫激活 (MIA) 导致的细胞因子水平升高，会增加 SZ 的风险并降低皮质 PV 水平。这些数据表明，产前暴露于 MIA 导致的细胞因子水平改变可能会破坏表达细胞因子受体的神经元的发育。由于 Lhx6 的缺失会引起细胞因子受体的缺陷，而 MIA 会降低 Lhx6 的水平，因此 Lhx6 缺陷和 MIA 的组合可能会严重破坏 PV 和 SST 神经元的发育。因此，我们假设具有 LGM 表型的 SZ 受试者中 PV 和 SST 神经元的紊乱反映了源自胎儿（即发育调节因子如 Lhx6 的缺陷）和/或母体（即免疫激活）的产前损伤的长期后果。检验这一中心假设需要采用跨物种的转化方法。在目标 1 中，我们将使用组织和细胞测量对 PFC PV 和 SST 神经元个体发育至关重要的发育因子和细胞因子受体的 mRNA 水平以及 SZ 和健康受试者 PFC 中的其他免疫标记物。我们假设，与其他 SZ 和健康受试者相比，具有 LGM 表型的 SZ 受试者表现出发育因子 mRNA 水平低和免疫标记物 mRNA 水平高的模式。 SZ 和双相情感障碍 (BP) 具有共同特征，包括遗传风险、精神病、认知障碍以及 PFC PV 和 GAD67 mRNA 水平低。在目标 2 中，我们将通过在 BP 受试者中进行类似于目标 1 的 mRNA 研究，来研究共同的发病机制是否可能破坏 PV&SST 神经元个体发育。我们假设 LGM 表型和发育因素缺陷也存在于 BP 受试者的子集中，但频率低于 SZ。最后，在目标 3 中，我们将通过给予怀孕野生型小鼠（Lhx6+/- 雄性祖细胞）诱导细胞因子反应的 Poly I:C 来研究可能导致 LGM 表型的潜在发病机制，并在后代中进行 PFC PV&SST 神经元发育调节剂和神经生理学测量的研究。我们假设 Lhx6 或 MIA 的缺陷独立存在，并且它们的相互作用更严重，导致成年 PV 和 SST 神经元的缺陷，类似于 LGM 表型中所见的缺陷。