The role of the hippocampal CA2 region in neuropsychiatric disease

海马CA2区在神经精神疾病中的作用

• 批准号: 9195134
• 负责人: STEVEN A SIEGELBAUM
• 金额: $ 41.41万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-14 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195134
• 关键词: Address; Adolescence; Affect; Animals; Area; Behavior; Behavioral; Bipolar Disorder; Brain; Brain region; Characteristics; Cognitive; Deletion Mutation; Development; Disease; Electrophysiology (science); Gene Expression Profile; Genetic; Genetic Models; Hippocampus (Brain); Human; Hyperactive behavior; Impairment; Individual; Lead; Learning; Link; Measures; Mediating; Membrane; Membrane Potentials; Memory; Memory impairment; Meta-Analysis; Modernization; Molecular; Motivation; Mus; Mutant Strains Mice; Neurodevelopmental Disorder; Neurons; Neurophysiology - biologic function; Output; Parvalbumins; Pathologic; Phenotype; Potassium Channel; Property; Reporting; Rest; Role; Schizophrenia; Short-Term Memory; Small Interfering RNA; Social Behavior; Social Behavior Disorders; Testing; Tetanus Toxin; Tracer; Transgenic Mice; Viral; Wild Type Mouse; autism spectrum disorder; behavioral impairment; cognitive change; cognitive function; conotruncal anomaly face syndrome; dentate gyrus; developmental disease; developmental genetics; disease phenotype; emerging adult; experimental study; hippocampal pyramidal neuron; inhibitory neuron; insight; interest; knock-down; mouse model; neural circuit; neuropsychiatric disorder; novel; overexpression; prepulse inhibition; public health relevance; receptor; relating to nervous system; response; social

 DESCRIPTION (provided by applicant): This project examines the inhibitory neural circuitry of the CA2 region of the hippocampus and its role in neuropsychiatric disorders, focusing on neurodevelopmental disease including schizophrenia (SCZ) and autism spectrum disorder (ASD). The motivation for this proposal comes from two independent findings. First, we have recently found that CA2 is crucial for social memory, the ability of an animal to recognize a conspecific. Given the altered social behaviors characteristic of SCZ and ASD, we postulated that pathological changes in CA2 function might be contributing factors. Indeed, two independent studies on the brains of individuals with SCZ and bipolar disorder have found a significant loss in the number of parvalbumin positive (PV+) inhibitory neurons in the CA2 region of the hippocampus, but not in neighboring hippocampal regions (CA1 and CA3). To examine the possible role of CA2 in SCZ, we examined a mouse model (Df(16)A+/- mice) of the human 22q11.2 deletion syndrome, a neurodevelopmental disorder that provides one of the strongest known genetic links with SCZ. Individuals harboring this deletion also display a number of autistic-like changes in social behaviors. The Df(16)A+/- mice were shown to have a number of cognitive changes associated with SCZ, including altered prepulse inhibition and contextual and working memory. Our preliminary results demonstrate that these mice also have a profound deficit in social memory. Remarkably, we find that the Df(16)A+/- mice show a specific reduction in PV+ inhibitory neurons in CA2, but no change in CA1 or CA3, identical to the results in human neuropsychiatric disorders. Moreover, the loss of inhibition in mice is first seen in late adolescence to early adulthood, similar to the developmental onset of SCZ. Here we will expand upon these initial findings by examining the importance of CA2 in the behavioral phenotypes of the Df(16)A+/- mice. We will first explore in more detail the function of CA2 inhibitory neurons that are targeted by the deletion mutation. We will also probe more deeply the behavioral changes in the Df(16)A+/- mice and ask whether we can rescue the behavioral changes by either silencing or activating CA2 in these animals. Thus the experiments we propose will both provide new insight into the neural circuitry and function of inhibition in the underexplored CA2 region of the hippocampus and will help determine the potential role of altered CA2 function in a mouse model of SCZ. These experiments offer the possibility of identifying new targets for treating disease, particularly as CA2 PNs display a unique pattern of gene expression not seen in other hippocampal areas. Given the changes in social behavior associated with other neuropsychiatric disorders, including ASD, our experiments may also provide general insights into basic brain mechanisms contributing to a variety of disorders of social behavior.

 描述（由申请人提供）：本项目研究海马CA 2区的抑制性神经回路及其在神经精神障碍中的作用，重点是神经发育疾病，包括精神分裂症（SCZ）和自闭症谱系障碍（ASD）。这项建议的动机来自两个独立的发现。首先，我们最近发现CA 2对社会记忆至关重要，社会记忆是动物识别同种动物的能力。鉴于SCZ和ASD的社会行为特征改变，我们推测CA 2功能的病理变化可能是促成因素。事实上，两项对SCZ和双相情感障碍患者大脑的独立研究发现，海马CA 2区的小清蛋白阳性（PV+）抑制性神经元数量显著减少，但相邻海马区（CA 1和CA 3）的小清蛋白阳性（PV+）抑制性神经元数量没有减少。为了研究CA 2在SCZ中的可能作用，我们检查了人类22q11.2缺失综合征的小鼠模型（Df（16）A+/-小鼠），这是一种神经发育障碍，提供了与SCZ最强的已知遗传联系之一。携带这种缺失的个体在社会行为上也会表现出一些类似自闭症的变化。Df（16）A+/-小鼠显示出许多与SCZ相关的认知变化，包括改变的前脉冲抑制和上下文和工作记忆。我们的初步结果表明，这些小鼠在社会记忆方面也存在严重缺陷。值得注意的是，我们发现Df（16）A+/-小鼠在CA 2中显示PV+抑制性神经元的特异性减少，但在CA 1或CA 3中没有变化，与人类神经精神疾病的结果相同。此外，小鼠的抑制能力丧失首先见于青春期后期至成年早期，与SCZ的发育发作相似。在这里，我们将通过检查CA 2在Df（16）A+/-小鼠行为表型中的重要性来扩展这些初步发现。我们将首先更详细地探索CA 2抑制性神经元的功能，这些神经元是缺失突变的靶点。我们还将更深入地探索Df（16）A+/-小鼠的行为变化，并询问我们是否可以通过沉默或激活这些动物中的CA 2来挽救行为变化。因此，我们提出的实验将提供新的见解的神经回路和功能的抑制在未充分探索的海马CA 2区，并将有助于确定改变CA 2功能的SCZ小鼠模型中的潜在作用。这些实验提供了确定治疗疾病的新靶点的可能性，特别是因为CA 2 PN显示出在其他海马区看不到的独特基因表达模式。考虑到与其他神经精神疾病（包括ASD）相关的社会行为变化，我们的实验也可能为导致各种社会行为障碍的基本大脑机制提供一般性见解。