Alterations to corticothalamic circuitry in a mouse model of autism

自闭症小鼠模型中皮质丘脑回路的改变

• 批准号: 9152030
• 负责人: CHARLES C LEE
• 金额: $ 1.21万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-17 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9152030
• 关键词: Accounting; Affect; Area; Autistic Disorder; Behavior; Behavioral; Biological Models; Brain; CNTNAP1 gene; Cells; Cognitive deficits; Communication; Cortical Dysplasia; Development; Disease; Employee Strikes; Environmental Risk Factor; Exhibits; Foundations; Future; Genes; Genetic; Glutamates; Goals; Health; In Vitro; Individual; Investigation; Knockout Mice; Knowledge; Lead; Link; Methods; Mission; Motor; Mus; Mutation; Neurologic; Neurons; Outcome; Partial Epilepsies; Pathway interactions; Pattern; Perception; Phenotype; Physiological; Preparation; Preventive measure; Process; Property; Prosencephalon; Public Health; Research; Risk; Role; Sensory; Slice; Social Interaction; Synapses; Syndrome; Testing; Thalamic Nuclei; Thalamic structure; autism spectrum disorder; autistic behaviour; base; disability; improved; in vivo; innovation; migration; mouse model; nervous system disorder; neural circuit; neurobehavioral; optogenetics; patch clamp; prevent; prospective; relating to nervous system; research study; response; restrictive repetitive behavior; therapeutic target

 DESCRIPTION (provided by applicant): Autism spectrum disorders (ASDs) comprise a wide constellation of neurobehavioral conditions that arise from abnormal patterns of brain development. Several genetic and environmental factors predispose individuals to developing ASDs, each manifesting in certain core behaviors. The long-term goals of our research are to understand the relative contributions of these factors in producing the neural changes that underlie ASDs. The primary objective here is to characterize the alterations to cortical layer 5 projections in the CNTNAP2-/- mouse model of autism. The central hypothesis is that the aberrant migration of neurons to layer 5 in these mice results in enhanced sensorimotor activity from cortical layer 5 to the thalamus and motor centers. Several anatomical and behavioral features of autistic subjects have been identified, which forms the basis for the proposed investigation. The specific aims of the project are to: 1) Determine the neuroanatomical connections of the ectopic neurons that have migrated improperly to layer 5 in the primary sensory cortical areas of CNTNAP2-/- mice and 2) Assess the synaptic properties and functional topography of the layer 5 projections to the thalamus in CNTNAP2-/- mice. This study will utilize a mouse model of the disease to examine the resultant pathological alterations to these forebrain components, which are predicted to account for aspects of the core behaviors associated with ASDs: abnormal social interactions, reduced vocal communication, and repetitive and restrictive behaviors. The proposed experiments are expected to clarify the roles of these and other forebrain components in ASDs and guide our future investigations aimed at directly linking these morphological alterations with autism and ultimately restoring normal behavior in this model system. These experiments will have a positive impact by illuminating the previously unappreciated role of the corticothalamic pathways in ASDs.

 描述（由申请人提供）：自闭症谱系障碍（ASD）包括由大脑发育异常模式引起的一系列神经行为病症。一些遗传和环境因素使个体容易患上自闭症谱系障碍，每种因素都表现为某些核心行为。我们研究的长期目标是了解这些因素在产生自闭症谱系障碍的神经变化中的相对贡献。这里的主要目标是表征 CNTNAP2-/- 自闭症小鼠模型中皮质第 5 层投影的变化。核心假设是，这些小鼠中神经元向第 5 层的异常迁移导致从皮质第 5 层到丘脑和运动中心的感觉运动活动增强。自闭症受试者的一些解剖和行为特征已被确定，这构成了拟议调查的基础。该项目的具体目标是：1) 确定 CNTNAP2-/- 小鼠初级感觉皮层区域中异位神经元不正确迁移至第 5 层的神经解剖学连接；2) 评估 CNTNAP2-/- 小鼠丘脑第 5 层投射的突触特性和功能拓扑。这项研究将利用该疾病的小鼠模型来检查这些前脑成分所产生的病理改变，预计这些改变可以解释与自闭症谱系障碍相关的核心行为的各个方面：异常的社交互动、声音交流减少以及重复和限制性行为。所提出的实验有望阐明这些和其他前脑成分在自闭症谱系障碍中的作用，并指导我们未来的研究，旨在将这些形态改变与自闭症直接联系起来，并最终恢复该模型系统中的正常行为。这些实验将通过阐明皮质丘脑通路在自闭症谱系障碍中以前未被认识到的作用来产生积极的影响。

项目成果

Perineuronal Nets in the Prefrontal Cortex of a Schizophrenia Mouse Model: Assessment of Neuroanatomical, Electrophysiological, and Behavioral Contributions.

• DOI: 10.3390/ijms222011140
• 发表时间: 2021-10-15
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Sultana R;Brooks CB;Shrestha A;Ogundele OM;Lee CC
• 通讯作者: Lee CC

Stress-altered synaptic plasticity and DAMP signaling in the hippocampus-PFC axis; elucidating the significance of IGF-1/IGF-1R/CaMKIIα expression in neural changes associated with a prolonged exposure therapy.

• DOI: 10.1016/j.neuroscience.2017.04.008
• 发表时间: 2017-06-14
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Ogundele OM;Ebenezer PJ;Lee CC;Francis J
• 通讯作者: Francis J

A Putative Mechanism of Age-Related Synaptic Dysfunction Based on the Impact of IGF-1 Receptor Signaling on Synaptic CaMKIIα Phosphorylation.

• DOI: 10.3389/fnana.2018.00035
• 发表时间: 2018
• 期刊: Frontiers in neuroanatomy
• 影响因子: 2.9
• 作者: Ogundele OM;Pardo J;Francis J;Goya RG;Lee CC
• 通讯作者: Lee CC

Upregulated SK2 Expression and Impaired CaMKII Phosphorylation Are Shared Synaptic Defects Between 16p11.2del and 129S:Δdisc1 Mutant Mice.

SK2 表达上调和 CaMKII 磷酸化受损是 16p11.2del 和 129S:αdisc1 突变小鼠之间共有的突触缺陷。

• DOI: 10.1177/1759091418817641
• 发表时间: 2018
• 期刊: ASN neuro
• 影响因子: 4.7
• 作者: Sultana,Razia;Ghandi,Tanya;MDavila,Alexandra;Lee,CharlesC;Ogundele,OlalekanM
• 通讯作者: Ogundele,OlalekanM

CaMKIIα expression in a mouse model of NMDAR hypofunction schizophrenia: Putative roles for IGF-1R and TLR4.

• DOI: 10.1016/j.brainresbull.2017.11.007
• 发表时间: 2018-03
• 期刊: Brain research bulletin
• 影响因子: 3.8
• 作者: Ogundele OM;Lee CC
• 通讯作者: Lee CC