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

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):我们的中心假设是发育迟缓综合征(包括自闭症谱系障碍)导致整合性脑区域中突触功能的改变,从而导致异常行为表型。我们将在转基因大鼠模型中探索这一假设。SHANK 3的单倍不足导致神经发育变化,包括自闭症谱系障碍、注意力障碍、言语缺失或延迟、轻度至中度智力残疾和运动改变。SHANK 3蛋白形成突触后致密物的关键结构部分。由于与小鼠相比,大鼠和人类之间的生理学更接近,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更易处理的实验模型系统,当考虑药物开发时,在进行PK研究的相同物种中进行生物测定当然是有利的。我们已经使用锌指核酸酶来开发具有全长大鼠Shank 3基因破坏的基因工程大鼠。这代表了有史以来第一个遗传修饰的ASD大鼠模型,并允许我们对前额叶皮层进行详细研究,这是自闭症中非常重要的一个区域,在小鼠模型中不易研究。我们建议对该模型进行详细分析。我们计划用以下具体目标来检验我们的中心假设:1)Shank 3缺陷大鼠的前额叶功能的行为评估; 2)Shank 3缺陷大鼠的前额叶功能的电生理分析;以及,3)Shank 3缺陷大鼠的前额叶功能的神经病理学和神经化学研究。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,它在使用最先进的方法来理解PFC在ASD中的作用方面具有创新性,这是ASD模型系统中尚未详细研究的关键区域。对PFC的关注还允许研究输入PFC的神经元通路,包括首次对ASD啮齿动物模型中的前额叶-前额叶回路进行行为神经生理学评估。我们的高分辨率3D成像和分析神经元形态的方法下降到单脊柱的水平是非常新颖的。这种形式的分析将使我们能够识别Shank 3缺陷大鼠中受影响的分子靶点,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型触摸屏室对PFC功能进行详细分析。

项目成果

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Joseph D. Buxbaum其他文献

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
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
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:
    $ 45.79万
  • 项目类别:
Genomics of Autism in Latinx Ancestries
拉丁裔血统中自闭症的基因组学
  • 批准号:
    10582709
  • 财政年份:
    2022
  • 资助金额:
    $ 45.79万
  • 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:
    $ 45.79万
  • 项目类别:
Genomics of Autism in Latinx Ancestries
拉丁裔血统中自闭症的基因组学
  • 批准号:
    10357168
  • 财政年份:
    2022
  • 资助金额:
    $ 45.79万
  • 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:
    $ 45.79万
  • 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:
    $ 45.79万
  • 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:
    $ 45.79万
  • 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:
    8759307
  • 财政年份:
    2014
  • 资助金额:
    $ 45.79万
  • 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:
    $ 45.79万
  • 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:
    $ 45.79万
  • 项目类别:

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