Forebrain GABAergic cell-selective genetic manipulation in mice

小鼠前脑 GABA 能细胞选择性基因操作

基本信息

批准号：
7735214
负责人：
Kazutoshi Nakazawa
金额：
$ 51.24万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7735214
关键词：
Ablation Address Adolescence Affect Agitation Animals Antipsychotic Agents Anxiety Autopsy Behavior Behavioral Biological Neural Networks Bipolar Disorder Brain Calcium-Binding Proteins Cells Chronic Clinical Research Development Disease Dose Drug Delivery Systems Electrophysiology (science)Exhibits Functional disorder Genes Genetic Glutamate Receptor Glutamates Goals Hippocampus (Brain)Human Impaired cognition Interneuron function Interneurons Knock-out Knowledge Laboratories Learning Memory Memory impairment Mental disorders Modeling Modification Mus N-Methyl-D-Aspartate Receptors NMDA receptor antagonist NR1 gene Neurons Neurotransmitters Partner in relationship Parvalbumins Pathology Patients Phenotype Play Population Precipitation Property Prosencephalon Psychotic Disorders Rattus Research Risperidone Role Schizophrenia Short-Term Memory Social isolation Stress Symptoms System Transgenic Organisms Work behavior test day density frontal lobe gamma-Aminobutyric Acid genetic manipulation human NR1 protein insight mouse model mutant neuropsychiatry novel patch clamp postnatal receptor social synthetic enzyme transmission process

项目摘要

In this transgenic line developed by Juan Belforte et al, genetic elimination of the NMDARs begins at postnatal day 7 and is targeted to 50% of cortical and hippocampal GABAergic cells, primarily parvalbumin positive ones. Veronika Zsiros showed an absence of NMDA receptor channel currents in virtually all of the targeted cells by whole-cell patch-clamp recordings thus confirming via electrophysiology the functional knockout of this receptor. We then conducted an extensive battery of behavioral tests and found that the mutants exhibited a variety of psychiatric disease-like phenotypes. Early postnatal modification of inhibitory networks in this mouse model revealed psychomotor agitation, sensorimotor deficits, anhedonic behavior, anxiety-like behavior, and deficits in nesting and mating. In addition, we addressed cognitive impairments in learning-related tasks and found deficits in spatial working memory and short-term social memory. Notably, the working memory deficit was ameliorated by the antipsychotic drug, risperidone. We also observed an exacerbation of some mutant phenotypes following social isolation stress which may serve as a model for stress-induced precipitation of human psychiatric disorders. Interestingly, when NR1 was genetically ablated in the same population of cells after adolescence using a different strain, we observed no such behavioral phenotypes as described above, suggesting that early postnatal NR1 ablation is critical for the development of psychiatric disease-like behavior. These findings strongly support the notion that loss of NMDAR activity in cortical GABAergic interneurons during the early postnatal period leads to psychiatric disorder-like behavior. To identify how dysfunction of cortical inhibitory networks is manifest at the cellular level, we are now conducting electrophysiological recordings from freely moving animals. Through the development of this novel genetic system, we have been able to target a widely distributed neural network and demonstrate that perturbations of this system may play a causal role in the onset of neuropsychiatric disorders.

在 Juan Belforte 等人开发的转基因系中，NMDAR 的基因消除从出生后第 7 天开始，目标是 50% 的皮质和海马 GABA 能细胞，主要是小清蛋白阳性细胞。 Veronika Zsiros 通过全细胞膜片钳记录显示几乎所有靶细胞中都不存在 NMDA 受体通道电流，从而通过电生理学证实了该受体的功能性敲除。然后我们进行了一系列广泛的行为测试，发现突变体表现出多种类似精神疾病的表型。该小鼠模型的抑制网络的早期产后修饰揭示了精神运动性躁动、感觉运动缺陷、快感缺失行为、焦虑样行为以及筑巢和交配缺陷。此外，我们还解决了学习相关任务中的认知障碍，并发现了空间工作记忆和短期社交记忆的缺陷。值得注意的是，抗精神病药物利培酮改善了工作记忆缺陷。我们还观察到一些突变表型在社会隔离压力后恶化，这可能作为压力诱发人类精神疾病沉淀的模型。有趣的是，当青春期后使用不同菌株在同一细胞群中对 NR1 进行基因消除时，我们没有观察到上述行为表型，这表明出生后早期 NR1 消除对于精神疾病样行为的发展至关重要。这些发现有力地支持了这样的观点，即出生后早期皮质 GABA 能中间神经元 NMDAR 活性的丧失会导致类似精神疾病的行为。为了确定皮质抑制网络的功能障碍如何在细胞水平上表现出来，我们现在正在对自由活动的动物进行电生理记录。通过开发这种新型遗传系统，我们已经能够针对广泛分布的神经网络，并证明该系统的扰动可能在神经精神疾病的发生中发挥因果作用。