Illuminating the functions of CACNA2D4 in the brain

阐明 CACNA2D4 在大脑中的功能

• 批准号: 9813213
• 负责人: AMY LEE
• 金额: $ 15.45万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813213
• 关键词: Address; Affect; Affective; Animal Model; Antibodies; Anxiety; Behavior; Behavioral; Bipolar Disorder; Brain; CAV1 gene; Cell membrane; Cells; Cognitive; Complex; Defect; Disease; Epilepsy; Etiology; Failure; Future; Genes; Genetic; Genetic Transcription; Genetic study; Goals; Human Genetics; Immunohistochemistry; Impairment; In Situ Hybridization; Ion Channel Protein; Knockout Mice; Light; Maintenance; Mental Depression; Mission; Modeling; Mus; Mutation; Nervous system structure; Neurons; Neurophysiology - biologic function; Outcome; Outcomes Research; Patients; Phenotype; Play; Presynaptic Terminals; Process; Protein Family; Proteins; Research; Retina; Retinal Photoreceptors; Role; Schizophrenia; Shapes; Short-Term Memory; Signal Transduction; Site; Structure; Time; Variant; Vision; Visual; autism spectrum disorder; base; density; design; endophenotype; experimental study; extracellular; human disease; insight; knockout animal; loss of function; loss of function mutation; member; mouse model; neural circuit; neuropsychiatric disorder; neurotransmitter release; novel; painful neuropathy; polyclonal antibody; presynaptic; receptor; synaptogenesis; tool; voltage

Project Summary Variants in the genes that encode voltage-gated Ca2+ channels are consistently and robustly associated with schizophrenia, bipolar disorder, and autism spectrum disorder. One of these genes is CACNA2D4, an IDG-elibigle gene that encodes an extracellular Ca2+ channel subunit (2-4) expressed in both the brain and retina. In the case of the retina, it has been established that 2-4 is required for normal vision. By contrast, the role of this protein in the brain remains understudied; we known neither where in the brain it acts nor what functions it may have there. The long-term goal of this project is to understand how genetic alterations in Cav-channel contributes to the complex etiology of neuropsychiatric disorders. The overall objective of the proposed research is to establish the cellular distribution of 2-4 in the mouse brain and which behaviors are disrupted in mice lacking this protein. The specific aims are to (1) define the neural circuits that may be regulated by 2–4 in the mouse brain and (2) identify cognitive/affective phenotypes in 2-4 knock-out mice. To accomplish these aims, we will use antibodies against 2–4 in immunohistochemical analyses of mouse brain, and behavioral analyses designed to uncover alterations in cognitive or affective function in mice.

项目概要 编码电压门控 Ca2+ 通道的基因变异体始终如一且稳健 与精神分裂症、双向情感障碍和自闭症谱系障碍有关。其中之一 基因是 CACNA2D4，一种编码细胞外 Ca2+ 通道的 IDG-elibigle 基因 亚基 (2-4) 在大脑和视网膜中都有表达。就视网膜而言， 确定正常视力需要 2-4。相比之下，这种蛋白质的作用 大脑仍未得到充分研究；我们既不知道它在大脑的哪个部位起作用，也不知道它的功能是什么 可能有。该项目的长期目标是了解基因改变如何 Cav通道中的Cav通道导致了神经精神疾病的复杂病因学。整体 本研究的目的是确定 α2β-4 在细胞中的分布 小鼠大脑以及缺乏这种蛋白质的小鼠的哪些行为会受到干扰。具体的 目标是 (1) 定义小鼠大脑中可能受 2–4 调节的神经回路 (2) 鉴定 2-4 敲除小鼠的认知/情感表型。为了完成这些 我们的目标是，我们将在小鼠的免疫组织化学分析中使用针对 2–4 的抗体 大脑和行为分析旨在揭示认知或情感的变化 在小鼠中发挥作用。