Parvalbumin-Containing Neurons in Schizophrenia

描述(申请人提供)：精神分裂症(SZ)患者含有钙结合蛋白小白蛋白(PV)的抑制神经元的神经回路发生功能改变。此外，前额叶皮质(PFC)的N-甲基-D-天冬氨酸(NMDA)受体对PV神经元的谷氨酸能神经传递可能缺乏SZ。在这项应用中，我们将研究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)GluR2亚基和代谢性I组谷氨酸受体mGluR1或5亚基，或多巴胺D1受体是否可能与NMDA神经递质缺陷有关。PV神经元上NMDA神经传递的缺陷可能通过至少两种机制进一步促进PV神经元的功能障碍：氧化应激和电压门控钾通道Kv3.1b和Kv3.2的表达减少，这在赋予PV神经元快峰特性方面起着关键作用。因此，我们将使用免疫印迹技术来检测促进氧化应激的两种酶，烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶(NADPH)和神经元型一氧化氮合酶(NNOS)，以及抗氧化酶谷氨酸半胱氨酸连接酶的催化和调节亚基。我们还将检测白介素6的mRNA在PV神经元中的表达，白介素6可以激活NOx的产生，从而促进氧化应激。此外，我们还将测量PV神经元中Kv3.1b和Kv3.2的mRNA，以了解它们在SZ是否会减少。由于PV神经元被富含蛋白多糖的软骨素蛋白多糖网(PNN)所包裹，PNN被认为在维持其功能完整性方面起着至关重要的作用，因此我们将研究SZ是否可能减少PNN的数量。最后，推测青春期PV神经元的缺陷可能破坏了皮质成熟的轨迹，从而导致SZ的发生。我们将探索在SZ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。综上所述，拟议中的实验结果将提高我们对SZ的病理生理学和可能有助于其发病的分子机制的理解。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.