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）中发生功能改变。此外，通过前额皮质（PFC） n -甲基- d -天冬氨酸（NMDA）受体在PV神经元上的谷氨酸神经传递可能在SZ中缺乏。在本应用中，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-异唑丙酸）GluR2亚基和代谢I组谷氨酸受体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神经元上的NMDA神经传递不足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的表达减少，这两种通道在赋予PV神经元快速尖峰特性中起关键作用。因此，我们将使用免疫印迹技术检测两种促进氧化应激的酶，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。我们还将检测PV神经元中激活Nox产生从而促进氧化应激的白细胞介素6 mRNA的表达。此外，我们将测量PV神经元中Kv3.1b和Kv3.2 mRNA的表达，以观察它们在SZ是否可能减少。由于PV神经元被富含硫酸软骨素蛋白多糖的神经周围网络（PNNs）包裹，这被认为在维持其功能完整性方面起着至关重要的作用，我们将研究SZ中PNNs的数量是否会减少。最后，我们假设青春期前后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。我们将探索在SZ和正常的青春期人类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，这些实验的发现将提高我们对SZ的病理生理和可能导致其发病的分子机制的理解。因此，它们可能导致概念化的治疗和预防策略，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. PUBLIC HEALTH RELEVANCE: The goal of this application is to improve our understanding of the molecular mechanisms that mediate the disturbances of inhibitory neural circuits in schizophrenia. Findings of the proposed studies are expected to shed light on the conceptualization of treatment and prevention strategies that aim at fundamentally correcting the underlying neural circuit deficits.