Parvalbumin-Containing Neurons in Schizophrenia

描述（由申请人提供）：含有钙结合蛋白小白蛋白（PV）的抑制性神经元的神经回路在精神分裂症（SZ）中发生功能性改变。此外，在 SZ 中，PV 神经元上通过前额皮质 (PFC) 中的 N-甲基-D-天冬氨酸 (NMDA) 受体的谷氨酸能神经传递可能存在缺陷。在本申请中，我们将检查其他谷氨酸受体亚基，包括 AMPA（1-氨基-3-羟基-5-甲基-4-异恶唑-丙酸酯）GluR2 亚基和代谢型 I 族谷氨酸受体 mGluR1 或 5 亚基，或多巴胺 D1 受体是否可能导致 NMDA 神经传递缺陷。 PV 神经元上 NMDA 神经传递缺陷可能通过至少两种机制进一步导致 PV 神经元功能障碍：氧化应激和电压门控钾通道 Kv3.1b 和 Kv3.2 表达减少，这在赋予 PV 神经元快速放电特性方面发挥着关键作用。因此，我们将使用免疫印迹技术来检查两种促进氧化应激的酶，即烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（Nox）和神经元一氧化氮合酶（nNOS），以及均质化PFC中抗氧化酶谷氨酸半胱氨酸连接酶的催化和调节亚基。我们还将检查白细胞介素 6 的 mRNA 表达，白细胞介素 6 会激活 PV 神经元中 Nox 的产生，从而促进氧化应激。此外，我们将测量 PV 神经元中 Kv3.1b 和 Kv3.2 的 mRNA，看看它们在 SZ 中是否会减少。由于 PV 神经元被富含硫酸软骨素蛋白聚糖的神经周围网 (PNN) 包裹，人们认为这些网络在维持其功能完整性方面发挥着至关重要的作用，因此我们将检查 SZ 中 PNN 的数量是否可能减少。最后，据推测，青春期前后 PV 神经元的缺陷可能会破坏皮质成熟的轨迹，从而导致 SZ 的发生。我们将探索 SZ 中和正常青春期人类 PFC 发育过程中 PV 神经元回路的转录调控，以深入了解 SZ 发病的可能分子机制。总而言之，所提出的实验结果将提高我们对 SZ 病理生理学以及可能导致其发生的分子机制的理解。因此，它们可能导致治疗和预防策略的概念化，旨在从根本上纠正或重新校准功能失调的 PV 神经元回路。

DESCRIPTION (provided by applicant): Neural circuits of inhibitory neurons that contain the calcium-binding protein parvalbumin (PV) are functionally altered in schizophrenia (SZ). Furthermore, it appears that glutamatergic neurotransmission on PV neurons via the N-methyl-D-aspartate (NMDA) receptor in the prefrontal cortex (PFC) may be deficient in SZ. In this application, we will examine whether other glutamate receptor subunits, including the AMPA (1-amino- 3-hydroxyl-5-methyl-4-isoxazole-propionate) GluR2 subunit and the metabotropic group I glutamate receptor mGluR1 or 5 subunit, or the dopamine D1 receptor may contribute to NMDA neurotransmission deficiency. Deficient NMDA neurotransmission on PV neurons may further contribute to PV neuronal dysfunction via at least two mechanisms: oxidative stress and decreased expression of voltage-gated potassium channels Kv3.1b and Kv3.2, which play a critical role in conferring the fast-spiking properties to PV neurons. Hence, we will use immunoblot technique to examine two enzymes that promote oxidative stress, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) and neuronal nitric oxide synthase (nNOS), and the catalytic and modulatory subunits of the antioxidant enzyme glutamate cysteine ligase in homogenized PFC. We will also examine the expression of the mRNA for interleukin 6, which activates Nox production and thus promote oxidative stress, in PV neurons. In addition, we will measure the mRNA for Kv3.1b and Kv3.2 in PV neurons to see if they may be decreased in SZ. Because PV neurons are ensheathed by chondroitin sulfate proteoglycans-rich perineuronal nets (PNNs), which are thought to play a crucial role in maintaining their functional integrity, we will examine whether the number of PNNs may be decreased in SZ. Finally, it is postulated that deficits of PV neurons during the peri-adolescent period may derail the trajectories of cortical maturation, contributing to the onset of SZ. We will explore the transcriptional regulation of PV neuronal circuits both in SZ and during normal peri-adolescent human PFC development in order to gain insight into the possible molecular mechanisms of SZ onset. Taken together, findings from the proposed experiments will improve our understanding of the pathophysiology of SZ and the molecular mechanisms that may contribute to its onset. As such, they may lead to the conceptualization of treatment and prevention strategies that aim at fundamentally correcting or recalibrating the dysfunctional PV neuronal circuits.