Prefrontal function in the Shank3-deficient rat: A first rat model for ASD

Shank3 缺陷大鼠的前额叶功能：第一个自闭症谱系障碍 (ASD) 大鼠模型

• 批准号: 9093835
• 负责人: Joseph D. Buxbaum
• 金额: $ 45.79万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9093835
• 关键词: 3-Dimensional; Affect; Animal Model; Animals; Area; Array tomography; Attention; Attentional deficit; Autistic Disorder; Beds; Behavior; Behavior assessment; Behavioral; Biochemical; Biological Assay; Biological Models; Brain region; Cognitive; Communication; Development; Developmental Delay Disorders; Disease; Disease model; Drug Industry; Drug Kinetics; Eating; Electrons; Electrophysiology (science); Experimental Models; Genes; Genetic Engineering; Glutamates; Goals; Health; Hippocampus (Brain); Human; Impaired cognition; In Vitro; Intellectual functioning disability; Investigation; Lead; Learning; Length; Link; Medial; Methods; Mission; Modeling; Molecular; Molecular Target; Morphology; Motor; Mus; Neurobiology; Neurodevelopmental Disorder; Neurons; Neuropsychology; Outcome; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Physiology; Prefrontal Cortex; Property; Proteins; Public Health; Rattus; Research; Resolution; Reversal Learning; Rodent Model; Role; Slice; Social Behavior; Social Functioning; Speech Delay; Structure; Symptoms; Synapses; Synaptic Receptors; Syndrome; System; Techniques; Testing; Three-Dimensional Imaging; Three-dimensional analysis; United States National Institutes of Health; Vertebral column; Work; autism spectrum disorder; base; behavioral outcome; behavioral study; cognitive function; density; drug development; feeding; flexibility; in vivo; innovation; memory recognition; mouse model; neurochemistry; neurophysiology; neurotransmission; new therapeutic target; novel; novel therapeutics; postsynaptic; pre-clinical; protein expression; relating to nervous system; social; synaptic function; therapeutic target; touchscreen; transmission process; zinc finger nuclease

DESCRIPTION (provided by applicant): Our central hypothesis is that developmental delay syndromes including autism spectrum disorders lead to alterations in synaptic function in integrative brain regions that result in aberrant behavioral phenotypes. We will explore this hypothesis in a genetically modified rat model. Haploinsufficiency of SHANK3 leads to neurodevelopmental changes that include autism spectrum disorders, attentional disorders, absent or delayed speech, mild to moderate intellectual disability, and motor alterations. The SHANK3 protein forms a key structural part of the postsynaptic density. Because of the closer physiology between rats and humans as compared to mice, rats remain the primary choice of the pharmaceutical industry for studying pharmacokinetic (PK) properties of novel drugs. In addition, rats provide a far more tractable experimental model system for neurobiological, electrophysiological and behavioral studies, and it is of course advantageous, when considering drug development, that the biological assays be done in the same species where the PK studies are carried out. We have used zinc-finger nucleases to develop a genetically engineered rat with a disruption in the full-length rat Shank3 gene. This represents a first-ever genetically modified rat model for ASD and permits us to carry out detail studies in the prefrontal cortex, an area of great importance in autism, not easily studied in mouse models. We propose to carry out a detailed analysis of this model. We plan to test our central hypothesis with the following specific aims: 1) Behavioral assessment of prefrontal function in Shank3-deficient rats; 2) Electrophysiological analysis of prefrontal function in Shank3-deficient rats; and, 3) Neuropathological and neurochemical investigation of prefrontal function in Shank3-deficient rats. 3) The research is innovative, in our opinion, because it will make use of a first-ever rat model of ASD. In addition, it is innovative in the use of state-of-the art approaches to understanding the role of PFC in ASD, a key region not yet studied in detail in ASD model systems. The focus on PFC also allows for studying neuronal pathways that feed into the PFC, including the first-ever behavioral neurophysiological assessment of hippocampal-prefrontal circuitry in a rodent model for ASD. Our approach to high-resolution 3D imaging and analysis of neuronal morphology down to the level of single spine is notably novel. This form of analysis will allow us to identify molecular targets that are affected in Shank3-deficient rats, in particular, te distribution of excitatory receptors and synaptic proteins known to be linked to spine and synapse size and maturity. Finally, our behavioral analyses will make use of novel touchscreen chambers for detailed analysis of PFC function.

描述（由申请人提供）：我们的中心假设是，包括自闭症谱系障碍在内的发育延迟综合症会导致综合大脑区域突触功能的改变，从而导致异常行为表型。我们将在基因修饰的大鼠模型中探讨这一假设。 Shank3的单倍不足会导致神经发育的变化，包括自闭症谱系障碍，注意力障碍，缺乏或延迟的语音，轻度到中度的智力障碍和运动改变。 Shank3蛋白构成突触后密度的关键结构部分。由于与小鼠相比，大鼠和人之间的生理较近，因此大鼠仍然是研究新药的药代动力学（PK）特性的制药行业的主要选择。此外，大鼠为神经生物学，电生理学和行为研究提供了更容易触发的实验模型系统，并且在考虑药物开发时，在同一PK研究的同一物种中进行生物学测定时，当然是有利的。我们已经使用锌指核酸酶开发了全长大鼠shank3基因的基因工程大鼠。这代表了ASD的第一个转基因大鼠模型，并允许我们在前额叶皮层中进行细节研究，这是自闭症中非常重要的领域，在小鼠模型中不易研究。我们建议对该模型进行详细的分析。我们计划以以下特定目的测试中心假设：1）尚克3缺陷大鼠的前额叶功能的行为评估； 2）尚克3缺陷大鼠的前额叶功能的电生理分析； 3）尚克3缺陷大鼠的前额叶功能的神经病理和神经化学研究。 3）我们认为，这项研究具有创新性，因为它将利用有史以来第一个ASD的大鼠模型。此外，它在使用最先进的方法来理解PFC在ASD中的作用是创新的，ASD是ASD模型系统中尚未详细研究的关键区域。对PFC的重点还允许研究进食PFC的神经元途径，包括在ASD的啮齿动物模型中对海马 - 前额外回路的首次行为神经生理评估。我们对高分辨率3D成像的方法和神经形态的分析至单脊的水平，显然是新颖的。这种分析形式将使我们能够鉴定出在Shank3缺陷型大鼠中受影响的分子靶标，特别是，兴奋受体的TE分布和已知与脊柱和突触大小和成熟度有关的突触蛋白。最后，我们的行为分析将利用新颖的触摸屏室进行详细的PFC功能分析。