Cellular Sources Of Neuregulin 1 (NRG1) Regulating Neural Activity And Behavior

调节神经活动和行为的神经调节蛋白 1 (NRG1) 的细胞来源

基本信息

批准号：
9321914
负责人：
CLARE M BERGSON
金额：
$ 22.8万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321914
关键词：
Affect Astrocytes Attenuated Behavior Brain Breeding Cell physiology Cells Chimeric Proteins Drug Design Enterobacteria phage P1 Cre recombinase Epilepsy Epileptogenesis Equilibrium ErbB4 gene Estrogen Receptors Exploratory Behavior Family Genes Glial Fibrillary Acidic Protein Glutamate Decarboxylase Goals Hippocampus (Brain)Hyperactive behavior Impairment Interneurons Knockout Mice Knowledge Learning LoxP-flanked allele Measures Memory Mus Neuregulin 1 Neurons Outcome Pain Parvalbumins Pathologic Patients Performance Play Population Process RNA Interference Receptor Protein-Tyrosine Kinases Role Schizophrenia Seizures Short-Term Memory Signal Transduction Slice Societies Source Synapses Synaptic Transmission Synaptic plasticity Tamoxifen Testing cell type cognitive enhancement cognitive function cost excitatory neuron executive function gamma-Aminobutyric Acid improved information processing insight knowledge base neuromechanism neurotrophic factor prepulse inhibition receptor relating to nervous system therapeutic target transmission process

项目摘要

Project Summary Schizophrenia (Sz) affects 1% of the population worldwide and places a costly and painful burden on patients, their families and society. Currently there are no treatments available to effectively rehabilitate Sz patients. The neurotrophic factor Neuregulin 1 (NRG1) is a promising therapeutic target because the gene is associated with Sz in various populations, and NRG1 levels are altered in Sz. NRG1 stimulates the ErbB family of tyrosine kinase receptors, including ErbB4, which is associated with Sz. NRG1 signaling via ErbB4 receptors expressed in parvalbumin (PV)-positive interneurons promotes neural processes important for executive functions which are impaired in Sz. A critical barrier to progress in improving treatment of Sz is a lack of understanding of whether the cells, which produce the NRG1 resulting in release of GABA or stimulation of gamma oscillations, also supply the NRG1 involved in suppression of LTP or seizure activity. Our goal is to improve the treatment of Sz by obtaining the information and understanding needed for designing drugs capable of quelling seizures without inhibiting neural mechanisms involved in learning and memory. Our central hypothesis is that different cellular sources of NRG1 differentially and selectively impact synaptic transmission, network activity and behavior, and that these unique cellular functions are potential mechanisms by which NRG1 could suppress seizures as well as promote network activity important for higher brain functions. Our objectives are to 1) determine the cell-type specific roles of neuronal and astrocytic NRG1 in GABA transmission, gamma oscillations, LTP, epileptogenesis, and Sz-relevant mouse behaviors and 2) provide clarification of the cellular sources of NRG1 involved in mechanisms regulating excitatory-inhibitory balance within local circuits, and facilitating transfer of information from hippocampus to cortex. Our expected outcomes include 1) knowledge of the cellular origins of NRG1 engaged during different states of synaptic and network activity, 2) improved understanding of the neuronal and astrocytic mechanisms underpinning NRG1 activation of ErbB4, and 3) new insights into the specific roles played by astrocytic and neuronal NRG1 in behaviors requiring cognitive functions often impaired in Sz. The impact of our findings will provide a stronger rationale for therapeutically targeting NRG1 during pathological conditions, as well as an improved knowledge base, which is needed for designing drugs capable of quelling seizures without inhibiting neural mechanisms involved in learning and memory. Aim 1 will test the hypothesis that NRG1 derived from principal neurons, interneurons and astrocytes differentially regulates excitatory and inhibitory synaptic transmission. Aim 2 will test the hypothesis that NRG1 derived from these three different cell types differentially regulate Sz-relevant behaviors.

项目摘要精神分裂症（SZ）影响全球1％的人口，并给患者带来昂贵而痛苦的负担，他们的家庭和社会。目前尚无可用的治疗方法来有效地修复SZ患者。这神经营养因子神经蛋白1（NRG1）是一个有前途的治疗靶标，因为该基因与 SZ中各种人群中的SZ和NRG1水平发生了变化。 NRG1刺激ERBB酪氨酸家族激酶受体，包括与SZ相关的ERBB4。通过ERBB4受体的NRG1信号传导在parvalbumin（PV）中 - 阳性中间神经元促进神经过程对执行功能很重要的神经过程在SZ中受到损害。改善SZ治疗的进展的关键障碍是对产生NRG1的细胞是释放GABA还是γ振荡的刺激，还提供参与LTP或癫痫活性抑制的NRG1。我们的目标是改善治疗通过获取设计能够平息癫痫发作的药物所需的信息和理解来通过不抑制学习和记忆涉及的神经机制。我们的中心假设是 NRG1的不同蜂窝源差异化并有选择地影响突触传播，网络活动和行为，并且这些独特的细胞函数是NRG1可以通过的潜在机制抑制癫痫发作，并促进网络活动对于更高的大脑功能很重要。我们的目标是到1）确定神经元和星形胶质细胞NRG1在GABA传播中的细胞类型特异性作用振荡，LTP，癫痫发生和相关的小鼠行为，2）阐明了细胞 NRG1的来源涉及调节当地电路内兴奋性抑制平衡的机制，促进信息从海马到皮质的转移。我们的预期结果包括1）知识在突触和网络活动的不同状态下参与的NRG1的细胞起源，2）改进了解基于ERBB4的NRG1激活的神经元和星形细胞机制，3）对星形胶质细胞和神经元NRG1在需要认知的行为中扮演的特定角色的见解 SZ中通常受损的功能。我们发现的影响将为治疗提供更强的理由在病理条件下靶向NRG1，以及改善的知识库，这是需要的设计能够打断癫痫发作的药物，而不会抑制学习和记忆。 AIM 1将检验以下假设，即NRG1衍生自主神经元，中间神经元和星形胶质细胞差异调节兴奋性和抑制性突触传播。 AIM 2将检验NRG1的假设从这三种不同的细胞类型衍生而来，对SZ相关行为进行了不同的调节。