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
基本信息
- 批准号:8759307
- 负责人:
- 金额:$ 54.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-01 至 2019-06-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAffectAnimal ModelAnimalsAreaAttentionAttentional deficitAutistic DisorderBedsBehaviorBehavior assessmentBehavioralBiochemicalBiological AssayBiological ModelsBrain regionCognitiveCommunicationDevelopmentDevelopmental Delay DisordersDiseaseDisease modelDrug IndustryDrug KineticsEatingElectronsExperimental ModelsGenesGenetic EngineeringGlutamatesGoalsHippocampus (Brain)HumanImpaired cognitionIn VitroIntellectual functioning disabilityInvestigationLeadLearningLengthLinkMedialMethodsMissionModelingMolecularMolecular TargetMorphologyMotorMusNeurobiologyNeurodevelopmental DisorderNeuronsNeuropsychologyOutcomePathway interactionsPatientsPatternPharmaceutical PreparationsPhenotypePhysiologicalPhysiologyPlasticsPrefrontal CortexPropertyProteinsPublic HealthRattusResearchResolutionReversal LearningRodent ModelRoleSliceSocial BehaviorSocial FunctioningSpeech DelayStructureSymptomsSynapsesSynaptic ReceptorsSyndromeSystemTechniquesTestingThree-Dimensional ImagingThree-dimensional analysisUnited States National Institutes of HealthVertebral columnWorkZinc Fingersautism spectrum disorderbasecognitive functiondensitydrug developmentfeedingflexibilityin vivoinnovationmemory recognitionmouse modelneurochemistryneurophysiologyneurotransmissionnew therapeutic targetnovelnovel therapeuticsnucleasepostsynapticpre-clinicalprotein expressionpublic health relevancerelating to nervous systemsocialsynaptic functiontherapeutic targettomographytouchscreentransmission process
项目摘要
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迟缓综合征导致综合脑区域突触功能的改变,从而导致异常的行为表型。我们将在转基因大鼠模型中探索这一假设。SHANK3单倍体缺陷导致神经发育变化,包括自闭症谱系障碍、注意力障碍、语言缺失或延迟、轻度至中度智力残疾和运动改变。SHANK3蛋白是突触后密度的关键结构部分。由于与小鼠相比,大鼠与人的生理更接近,因此大鼠仍然是制药行业研究新药药代动力学(PK)特性的主要选择。此外,大鼠为神经生物学、电生理学和行为学研究提供了一个更容易处理的实验模型系统,在考虑药物开发时,在进行PK研究的同一物种中进行生物分析当然是有利的。我们利用锌指核酸酶培育了一只全长大鼠Shank3基因被破坏的基因工程大鼠。这代表了有史以来第一个ASD的转基因大鼠模型,并允许我们对前额皮质进行详细的研究,前额皮质是自闭症中非常重要的区域,不容易在小鼠模型中研究。我们建议对这个模型进行详细的分析。我们计划以以下具体目标来验证我们的中心假设:1)shank3缺陷大鼠前额叶功能的行为评估;2) shank3缺陷大鼠前额叶功能电生理分析;3) shank3缺陷大鼠前额叶功能的神经病理和神经化学研究。3)在我们看来,这项研究是创新的,因为它将利用有史以来第一个ASD大鼠模型。此外,它还创新地使用了最先进的方法来理解PFC在ASD中的作用,这是ASD模型系统中尚未详细研究的关键区域。对PFC的关注也允许研究进入PFC的神经元通路,包括首次在ASD啮齿动物模型中对海马-前额叶回路进行行为神经生理学评估。我们的方法高分辨率的3D成像和神经元形态分析下降到单个脊柱的水平是值得注意的新颖。这种形式的分析将使我们能够确定在shank3缺陷大鼠中受影响的分子靶标,特别是已知与脊柱和突触大小和成熟度相关的兴奋性受体和突触蛋白的分布。最后,我们的行为分析将利用新颖的触摸屏室来详细分析PFC功能。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Joseph D. Buxbaum其他文献
Contribution of autosomal rare and emde novo/em variants to sex differences in autism
常染色体罕见及新发变异对自闭症性别差异的影响
- DOI:
10.1016/j.ajhg.2025.01.016 - 发表时间:
2025-03-06 - 期刊:
- 影响因子:8.100
- 作者:
Mahmoud Koko;F. Kyle Satterstrom;Branko Aleksic;Mykyta Artomov;Mafalda Barbosa;Elisa Benetti;Catalina Betancur;Monica Biscaldi-Schafer;Anders D. Børglum;Harrison Brand;Alfredo Brusco;Joseph D. Buxbaum;Gabriele Campos;Simona Cardaropoli;Diana Carli;Angel Carracedo;Marcus C.Y. Chan;Andreas G. Chiocchetti;Brian H.Y. Chung;Brett Collins;Hilary Martin - 通讯作者:
Hilary Martin
The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders
- DOI:
10.1016/j.tins.2009.04.003 - 发表时间:
2009-07-01 - 期刊:
- 影响因子:
- 作者:
Catalina Betancur;Takeshi Sakurai;Joseph D. Buxbaum - 通讯作者:
Joseph D. Buxbaum
Familial confounding in the associations between maternal health and autism
母亲健康与自闭症之间关联中的家族混杂
- DOI:
10.1038/s41591-024-03479-5 - 发表时间:
2025-01-31 - 期刊:
- 影响因子:50.000
- 作者:
Vahe Khachadourian;Elias Speleman Arildskov;Jakob Grove;Paul F. O’Reilly;Joseph D. Buxbaum;Abraham Reichenberg;Sven Sandin;Lisa A. Croen;Diana Schendel;Stefan Nygaard Hansen;Magdalena Janecka - 通讯作者:
Magdalena Janecka
Genome-wide analyses identify 30 loci associated with obsessive–compulsive disorder
全基因组分析确定了 30 个与强迫症相关的基因位点
- DOI:
10.1038/s41588-025-02189-z - 发表时间:
2025-05-13 - 期刊:
- 影响因子:29.000
- 作者:
Nora I. Strom;Zachary F. Gerring;Marco Galimberti;Dongmei Yu;Matthew W. Halvorsen;Abdel Abdellaoui;Cristina Rodriguez-Fontenla;Julia M. Sealock;Tim Bigdeli;Jonathan R. Coleman;Behrang Mahjani;Jackson G. Thorp;Katharina Bey;Christie L. Burton;Jurjen J. Luykx;Gwyneth Zai;Silvia Alemany;Christine Andre;Kathleen D. Askland;Julia Bäckman;Nerisa Banaj;Cristina Barlassina;Judith Becker Nissen;O. Joseph Bienvenu;Donald Black;Michael H. Bloch;Sigrid Børte;Rosa Bosch;Michael Breen;Brian P. Brennan;Helena Brentani;Joseph D. Buxbaum;Jonas Bybjerg-Grauholm;Enda M. Byrne;Judit Cabana-Dominguez;Beatriz Camarena;Adrian Camarena;Carolina Cappi;Angel Carracedo;Miguel Casas;Maria Cristina Cavallini;Valentina Ciullo;Edwin H. Cook;Jesse Crosby;Bernadette A. Cullen;Elles J. De Schipper;Richard Delorme;Srdjan Djurovic;Jason A. Elias;Xavier Estivill;Martha J. Falkenstein;Bengt T. Fundin;Lauryn Garner;Christina Gironda;Fernando S. Goes;Marco A. Grados;Jakob Grove;Wei Guo;Jan Haavik;Kristen Hagen;Kelly Harrington;Alexandra Havdahl;Kira D. Höffler;Ana G. Hounie;Donald Hucks;Christina Hultman;Magdalena Janecka;Eric Jenike;Elinor K. Karlsson;Kara Kelley;Julia Klawohn;Janice E. Krasnow;Kristi Krebs;Christoph Lange;Nuria Lanzagorta;Daniel Levey;Kerstin Lindblad-Toh;Fabio Macciardi;Brion Maher;Brittany Mathes;Evonne McArthur;Nathaniel McGregor;Nicole C. McLaughlin;Sandra Meier;Euripedes C. Miguel;Maureen Mulhern;Paul S. Nestadt;Erika L. Nurmi;Kevin S. O’Connell;Lisa Osiecki;Olga Therese Ousdal;Teemu Palviainen;Nancy L. Pedersen;Fabrizio Piras;Federica Piras;Sriramya Potluri;Raquel Rabionet;Alfredo Ramirez;Scott Rauch;Abraham Reichenberg;Mark A. Riddle;Stephan Ripke;Maria C. Rosário;Aline S. Sampaio;Miriam A. Schiele;Anne Heidi Skogholt;Laura G. Sloofman;Jan Smit;María Soler Artigas;Laurent F. Thomas;Eric Tifft;Homero Vallada;Nathanial van Kirk;Jeremy Veenstra-VanderWeele;Nienke N. Vulink;Christopher P. Walker;Ying Wang;Jens R. Wendland;Bendik S. Winsvold;Yin Yao;Hang Zhou;Arpana Agrawal;Pino Alonso;Götz Berberich;Kathleen K. Bucholz;Cynthia M. Bulik;Danielle Cath;Damiaan Denys;Valsamma Eapen;Howard Edenberg;Peter Falkai;Thomas V. Fernandez;Abby J. Fyer;J. M. Gaziano;Dan A. Geller;Hans J. Grabe;Benjamin D. Greenberg;Gregory L. Hanna;Ian B. Hickie;David M. Hougaard;Norbert Kathmann;James Kennedy;Dongbing Lai;Mikael Landén;Stéphanie Le Hellard;Marion Leboyer;Christine Lochner;James T. McCracken;Sarah E. Medland;Preben B. Mortensen;Benjamin M. Neale;Humberto Nicolini;Merete Nordentoft;Michele Pato;Carlos Pato;David L. Pauls;John Piacentini;Christopher Pittenger;Danielle Posthuma;Josep Antoni Ramos-Quiroga;Steven A. Rasmussen;Margaret A. Richter;David R. Rosenberg;Stephan Ruhrmann;Jack F. Samuels;Sven Sandin;Paul Sandor;Gianfranco Spalletta;Dan J. Stein;S. Evelyn Stewart;Eric A. Storch;Barbara E. Stranger;Maurizio Turiel;Thomas Werge;Ole A. Andreassen;Anders D. Børglum;Susanne Walitza;Kristian Hveem;Bjarne K. Hansen;Christian Rück;Nicholas G. Martin;Lili Milani;Ole Mors;Ted Reichborn-Kjennerud;Marta Ribasés;Gerd Kvale;David Mataix-Cols;Katharina Domschke;Edna Grünblatt;Michael Wagner;John-Anker Zwart;Gerome Breen;Gerald Nestadt;Jaakko Kaprio;Paul D. Arnold;Dorothy E. Grice;James A. Knowles;Helga Ask;Karin J. Verweij;Lea K. Davis;Dirk J. Smit;James J. Crowley;Jeremiah M. Scharf;Murray B. Stein;Joel Gelernter;Carol A. Mathews;Eske M. Derks;Manuel Mattheisen - 通讯作者:
Manuel Mattheisen
Rigor in science and science reporting: updated guidelines for submissions to Molecular Autism
- DOI:
10.1186/s13229-018-0249-x - 发表时间:
2019-02-22 - 期刊:
- 影响因子:5.500
- 作者:
Joseph D. Buxbaum;Simon Baron-Cohen;Evdokia Anagnostou;Chris Ashwin;Catalina Betancur;Bhismadev Chakrabarti;Jacqueline N. Crawley;Rosa A. Hoekstra;Patrick R. Hof;Meng-Chuan Lai;Michael V. Lombardo;Cynthia M. Schumann - 通讯作者:
Cynthia M. Schumann
Joseph D. Buxbaum的其他文献
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{{ truncateString('Joseph D. Buxbaum', 18)}}的其他基金
Pooled Optical Imaging, Neurite Tracing, and Morphometry Across Perturbations (POINT-MAP).
混合光学成像、神经突追踪和扰动形态测量 (POINT-MAP)。
- 批准号:
10741188 - 财政年份:2023
- 资助金额:
$ 54.44万 - 项目类别:
1/4 - The Autism Sequencing Consortium: Discovering autism risk genes and how they impact core features of the disorder
1/4 - 自闭症测序联盟:发现自闭症风险基因以及它们如何影响该疾病的核心特征
- 批准号:
10580072 - 财政年份:2022
- 资助金额:
$ 54.44万 - 项目类别:
1/4 - The Autism Sequencing Consortium: Autism Gene Discovery in >50,000 Exomes
1/4 - 自闭症测序联盟:在 >50,000 个外显子组中发现自闭症基因
- 批准号:
9217160 - 财政年份:2017
- 资助金额:
$ 54.44万 - 项目类别:
Development of Behavioral and Neural Biomarkers for Autism Spectrum Disorder Using a Genetically Defined Subtype
使用基因定义的亚型开发自闭症谱系障碍的行为和神经生物标志物
- 批准号:
9264590 - 财政年份:2016
- 资助金额:
$ 54.44万 - 项目类别:
Population-Based Autism Genetics and Environment Study
基于人群的自闭症遗传学和环境研究
- 批准号:
10132395 - 财政年份:2014
- 资助金额:
$ 54.44万 - 项目类别:
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 - 财政年份:2014
- 资助金额:
$ 54.44万 - 项目类别:
Population-Based Autism Genetics and Environment Study
基于人群的自闭症遗传学和环境研究
- 批准号:
9918463 - 财政年份:2014
- 资助金额:
$ 54.44万 - 项目类别:
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:
8880287 - 财政年份:2014
- 资助金额:
$ 54.44万 - 项目类别:
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