Investigations of Neuronal Ensembles and Shank3-Homer Scaffolds on Reward and Social Behavior in a Shank3 model of Autism

神经元集成和 Shank3-Homer 支架对自闭症 Shank3 模型中奖励和社会行为的研究

• 批准号: 10617704
• 负责人: Oakleigh Folkes
• 金额: $ 7.18万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617704
• 关键词: Behavior; Behavioral; Behavioral Paradigm; Binding; Biological Assay; Bipolar Disorder; Calcium; Characteristics; Cues; Data; Disease model; Dopamine D1 Receptor; Etiology; Exons; Fragile X Syndrome; Functional disorder; Genes; Genetic; Goals; Image; Immunohistochemistry; Investigation; Knock-out; Measures; Methodology; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Neurons; Nucleus Accumbens; Point Mutation; Population; Proline-Rich Domain; Proteins; Psychological reinforcement; Research; Research Domain Criteria; Research Personnel; Rewards; Risk Factors; Role; Scaffolding Protein; Schizophrenia; Social Behavior; Social Interaction; Synapses; Techniques; Testing; Time; Western Blotting; autism spectrum disorder; density; experimental study; in vivo; metabotropic glutamate receptor 5; mouse model; neural circuit; neuropsychiatric disorder; new therapeutic target; novel; optogenetics; post-doctoral training; postsynaptic; preference; recruit; response; scaffold; social; social deficits

PROPOSAL SUMMARY Deficits in social interaction are characteristic of several neuropsychiatric disorders, including Autism Spectrum Disorder (ASD). The cellular, molecular, and circuit mechanisms of social deficits in ASD are largely unknown and warrants further research. One of the most consistent etiological findings in ASD is a complete deletion of the SHANK3 gene, which encodes a postsynaptic scaffold protein in neurons. Our lab developed the first Shank3 complete knockout model by deleting exons 4-22 (Shank3∆e4-22). Shank3∆e4-22 mice show decreased social and reward-seeking behavior and blunted response of the Nucleus Accumbens (NAc) to social cues. The NAc is a well-established regulator of social behavior. Yet, the characteristics of neurons in the NAc that are active during social behavior, or social ensembles, are not well defined. ~95% of neurons in the NAc are medium-spiny neurons (MSNs) that express either dopamine receptor D1 (D1+), which encode reward reinforcement, or D2 (D2+), which encode aversive responses. NAc MSNs express high levels of SHANK3, and Shank3 deletion induces profound changes in D2+ MSN function. Taken together, this indicates a potential mechanism of action for social behavior deficits in Shank3∆e4-22 mice. SHANK3 scaffolds HOMER1b/c and metabotropic glutamate receptor 5 (mGluR5) to the postsynaptic density (PSD). HOMER1b/c and mGluR5 function in the NAc is crucial for regulating social and reward-seeking behaviors in WT mice. To study the role of SHANK3-HOMER1b/c interaction, our lab generated the first SHANK3-HOMER1b/c mutant mouse, Shank3PL. Since joining the Jiang lab, I have collected pilot data showing that Shank3PL mice have significantly decreased social and reward-seeking behavior. Pilot data also indicate Shank3PL mice have decreased HOMER1b/c expression in the PSD of the NAc. The specific objective of this proposal is to delineate how SHANK3 deficiency causes cellular and molecular malfunctions that underlie abnormal circuit and social behavior using our two novel mouse models: Shank3∆e4-22 and Shank3PL. First, I hypothesize that NAc social ensembles in Shank3∆e4-22 mice are primarily composed of D2+ MSNs and encode aversion and negative sociability; in contrast, I predict WT social ensembles are predominantly D1+ MSNs and encode reinforcement and positive social behavior. Second, I hypothesize that SHANK3-HOMER1b/c scaffolds are crucial for social and reward behavior. We will test these hypotheses using comprehensive methodologies. This study will be the first to characterize social ensembles in a well-validated genetic ASD model and the first to investigate the role of SHANK3-HOMER1b/c scaffolds on behaviors and NAc activity. Importantly, these studies may lead to the identification of novel therapeutic targets for treating social and reward deficits in ASD and other neuropsychiatric disorders.

提案摘要 社会交往的缺陷是几种神经精神疾病的特征，包括自闭症 谱系障碍（ASD）。ASD中社交缺陷的细胞、分子和电路机制主要是 未知，需要进一步研究。ASD中最一致的病因学发现之一是完全的 SHANK 3基因的缺失，该基因编码神经元中的突触后支架蛋白。我们的实验室开发了 通过删除外显子4-22（Shank 3外显子4 -22）的第一个Shank 3完全敲除模型。Shank 3 β 4 -22小鼠表现出降低的 社会和奖励寻求行为以及伏隔核（NAc）对社会线索的迟钝反应。 NAc是一个完善的社会行为监管机构。然而，NAc中神经元的特征 在社会行为中活跃的，或者说社会群体，并没有很好的定义。NAc中约95%的神经元 中棘神经元（MSN）表达多巴胺受体D1（D1+）， 强化，或D2（D2+），编码厌恶反应。NAc MSN表达高水平的SHANK 3，并且 Shank 3缺失诱导D2+ MSN功能的深刻变化。综合来看，这表明 Shank 3小鼠4 -22中社会行为缺陷的作用机制。 SHANK 3支架HOMER 1b/c和代谢型谷氨酸受体5（mGluR 5）到突触后 密度（PSD）。NAc中的HOMER 1b/c和mGluR 5功能对于调节社交和奖励寻求至关重要 WT小鼠的行为。为了研究SHANK 3-HOMER 1b/c相互作用的作用，我们的实验室产生了第一个 SHANK 3-HOMER 1b/c突变小鼠，Shank 3 PL。自从加入Jiang实验室以来，我收集的试验数据显示， Shank 3 PL小鼠的社交和奖励寻求行为显著减少。试点数据还表明， Shank 3 PL小鼠在NAc的PSD中具有降低的HOMER 1b/c表达。 这项提案的具体目标是描述SHANK 3缺陷如何导致细胞和 使用我们的两种新型小鼠模型，研究了导致异常电路和社会行为的分子故障： Shank 3手柄4 -22和Shank 3 PL。首先，我假设Shank 3小鼠4 -22中的NAc社会集合主要是 由D2+ MSN组成，编码厌恶和消极社交;相比之下，我预测WT社交 集合体主要是D1+ MSN，编码强化和积极的社会行为。二我 假设SHANK 3-HOMER 1b/c支架对于社会和奖励行为至关重要。我们将测试这些 使用综合方法的假设。 这项研究将是第一个在一个经过充分验证的遗传ASD模型中表征社会群体的研究， 首次研究SHANK 3-HOMER 1b/c支架对行为和NAc活性的作用。重要的是， 这些研究可能会导致识别新的治疗靶点，用于治疗社会和奖励缺陷， ASD和其他神经精神疾病。