Disrupted Ontogeny of Cortical GABA Neurons in Schizophrenia

项目摘要 精神分裂症（SZ）的认知障碍与抑制性前额叶皮层功能障碍有关 (PFC)回路，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SZ受试者的一个子集（约50%）中最为突出， “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受试者可能受到遗传责任和/或影响神经元的环境损伤的影响。 个体发育在人类中，胚胎PV和SST神经元表达发育调节因子（例如，Lhx 6）和 细胞因子受体调节其特化和迁移。我们最近发现PFC Lhx 6 在LGM SZ受试者中最显著的mRNA水平，表明低Lhx 6水平可能损害Lhx 6的表达。 SZ中PV和SST神经元的发育。此外，胎儿环境中的干扰，如升高的 由于母体免疫激活（MIA）导致的细胞因子水平升高，增加了SZ的风险，并降低了皮质PV水平。 这些数据表明，产前暴露于MIA引起的细胞因子水平改变可能会破坏MIA的发育。 表达细胞因子受体的神经元。由于Lhx 6的缺失诱导细胞因子受体和MIA的缺陷， 降低Lhx 6水平，Lhx 6缺陷和MIA的组合可能严重破坏PV和SST神经元 发展因此，我们假设在SZ受试者中PV和SST神经元的紊乱与 LGM表型反映了胎儿产前损伤的长期后果（即， 发育调节因子如Lhx 6）和/或母体（即免疫激活）来源。测试这个 中心假设需要一个翻译，跨物种的方法。在目标1中，我们将使用组织和细胞 测量PFC PV和SST神经元关键发育因子和细胞因子受体的mRNA水平 SZ和健康受试者PFC中的个体发育和其他免疫标志物。我们假设SZ受试者 与LGM表型显示模式的低mRNA水平的发展因素和高mRNA 相对于其他SZ和健康受试者的免疫标志物水平。SZ和双相情感障碍（BP）的份额 特征包括遗传风险、精神病、认知障碍和PFC PV和GAD 67 mRNA水平低。 在目标2中，我们将研究是否有一个共同的发病机制可能会破坏PV和SST神经元个体发育 通过在BP受试者中进行类似于Aim 1的mRNA研究。我们假设LGM表型和 发育因素的缺陷也存在于BP受试者的子集中，但频率较低 比SZ。最后，在目标3中，我们将研究可能导致LGM的潜在发病机制 通过给妊娠野生型小鼠（Lhx 6 +/-雄性）施用诱导细胞因子应答的聚I：C， PFC-PV和SST神经元发育调节因子和神经生理学的研究 在后代的措施。我们假设Lhx 6或MIA的缺陷是独立的，它们之间的相互作用 更严重的是，导致类似于在LGM表型中所见的成年PV&SST神经元的缺陷。

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.