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神经元的紊乱在被鉴定为“低GABA标记物”（LGM）分子表型的SZ受试者的子集（~50%）中最为突出。LGM SZ受试者中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育的遗传责任和/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，Lhx 6）和调节其特化和迁移的细胞因子受体。我们最近发现PFC Lhx 6 mRNA水平的赤字是最突出的LGM SZ科目，这表明低Lhx 6水平可能会损害PV和SST神经元的发展SZ。此外，胎儿环境的紊乱，如母体免疫激活（MIA）引起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，产前暴露于改变细胞因子水平由于MIA可能会破坏细胞因子受体表达神经元的发展。由于Lhx 6的缺失诱导细胞因子受体的缺陷并且MIA降低Lhx 6水平，Lhx 6缺陷和MIA的组合可能严重破坏PV&SST神经元发育。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起源于胎儿（即发育调节因子如Lhx 6的缺陷）和/或母体（即免疫激活）的产前损伤的长期后果。检验这一核心假设需要一种跨物种的翻译方法。在目标1中，我们将使用发育因子和细胞因子受体的mRNA水平的组织和细胞测量，这些因子和细胞因子受体对PFC PV和SST神经元个体发育以及SZ和健康受试者PFC中的其他免疫标志物至关重要。我们假设SZ受试者与LGM表型显示模式的低mRNA水平的发育因子和高mRNA水平的免疫标记物相对于其他SZ和健康受试者。SZ和双相情感障碍（BP）的共同特征包括遗传风险、精神病、认知障碍和PFC PV和GAD 67 mRNA水平低。在目标2中，我们将通过在BP受试者中进行类似于目标1的mRNA研究来调查是否有共同的发病机制可以破坏PV和SST神经元个体发育。我们假设，LGM表型和缺陷的发育因素也存在于一个子集的BP科目，但在较低的频率比SZ。最后，在目标3中，我们将通过给予poly I：C（诱导妊娠野生型小鼠（Lhx 6 +/-雄性祖细胞）的细胞因子反应）并进行PFC PV和SST的研究来研究可能导致LGM表型的潜在发病机制。后代的神经生理学措施。我们假设Lhx 6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&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.