Disrupted Ontogeny of Cortical GABA Neurons in Schizophrenia

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）回路功能障碍有关，包括小白蛋白（PV）和生长抑素（SST）神经元。我们最近发现PFC PV&SST神经元的紊乱在被鉴定为“低GABA标记”（LGM）分子表型的SZ受试者中最突出（约50%）。LGM SZ受试者PV&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生的遗传负担和/或环境损害的影响。在人类中，胚胎PV&SST神经元表达发育调节因子（如Lhx6）和细胞因子受体，调节其特异性和迁移。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，这表明低Lhx6水平可能会损害SZ PV&SST神经元的发育。此外，胎儿环境的干扰，如由于母体免疫激活（MIA）导致的细胞因子水平升高，增加了SZ的风险和较低的皮质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细胞因子受体表达神经元的发育。由于Lhx6的缺失导致细胞因子受体的缺陷，而MIA降低了Lhx6的水平，因此Lhx6缺陷和MIA的结合可能严重破坏PV&SST神经元的发育。因此，我们假设具有LGM表型的SZ受试者的PV&SST神经元的紊乱反映了胎儿（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。验证这一中心假设需要一种跨物种的翻译方法。在目标1中，我们将使用组织和细胞测量对SZ和健康受试者PFC中PV&SST神经元个体发育至关重要的发育因子和细胞因子受体mRNA水平以及其他免疫标志物。我们假设，与其他SZ和健康受试者相比，LGM表型的SZ受试者表现出发育因子mRNA水平低、免疫标志物mRNA水平高的模式。SZ和双相情感障碍（BP）具有遗传风险、精神病、认知障碍和低PFC PV和GAD67 mRNA水平等共同特征。在Aim 2中，我们将通过在BP受试者中进行类似Aim 1的mRNA研究，研究是否有一种共同的发病机制可能破坏PV&SST神经元的个体发生。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，但频率低于SZ。最后，在Aim 3中，我们将通过给妊娠野生型小鼠（Lhx6+/-雄性祖细胞）注射poly I:C诱导细胞因子反应，并对后代的PFC PV&SST神经元发育调节因子和神经生理学措施进行研究，研究可能导致LGM表型的潜在发病机制。我们假设Lhx6或MIA的独立缺陷，以及它们之间更严重的相互作用，导致成人PV&SST神经元的缺陷，类似于LGM表型中所见的缺陷。

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.