Generating mouse models with cell type-specific and reversible GABA deficiency
生成具有细胞类型特异性和可逆性 GABA 缺陷的小鼠模型
基本信息
- 批准号:10679713
- 负责人:
- 金额:$ 23.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAffectAreaBasal GangliaBypassCommunitiesCorpus striatum structureCre driverDiseaseDisinhibitionDopamineDopamine D1 ReceptorDopamine D2 ReceptorDrosophila genusElectrophysiology (science)ElementsEnzymesEpilepsyGap JunctionsGeneticGlutamate DecarboxylaseGlutamatesGoalsHealthHumanInjectionsInternal Ribosome Entry SiteInterneuronsKnock-outLoxP-flanked alleleMeasuresMediatingMemoryModelingMorphologyMotorMotor ActivityMotor outputMusMutationNational Institute of Mental HealthNational Institute of Neurological Disorders and StrokeNeonatalNervous SystemNeuronsNeuropeptidesNeurosciences ResearchNeurotransmittersParvalbuminsPathway interactionsPhysiologicalPropertyPyridoxal PhosphatePyridoxine 5 Phosphate OxidaseResearchReversal LearningSchizophreniaSeizuresShort-Term MemorySleepSynaptic ReceptorsTestingTyrosine 3-MonooxygenaseVitamin B6brain morphologycell typecofactordietarydopaminergic neurondrinkingexperimental studyfeasibility testingfeedinggamma-Aminobutyric Acidinhibitory neuronknockout genemotor learningmouse modelnovel strategiespostsynapticpresynapticresponsetooltransmission process
项目摘要
ABSTRACT
GABAergic neurons are the main inhibitory neurons in the adult nervous system. There are diverse cortical
and subcortical GABAergic interneurons and projection neurons with different physiological properties,
connectivity, and functions. However, few studies have been able to investigate the functions of specific
subclasses by perturbing GABA release selectively. We propose an approach to target GABA synthesis in
subclasses of GABAergic neurons. GAD activity requires the cofactor pyridoxal-5-phosphate (PLP). PLP
deficiency can be achieved by knocking out the rate limiting enzyme in PLP synthesis: pyridoxine-5-phosphate
oxidase (PNPO). Moreover, PLP deficiency can be rescued by systemic PLP administration. We therefore
propose to generate cell type specific PNPO deficiency mouse models. We will first generate models with
GABA deficiency in well-studied but highly distinct cell types to test the feasibility of our approach: 1) the
parvalbumin (PV)-positive GABAergic neurons; 2) the VIP-positive GABAergic neurons; 3) the striatal
dopamine D1 receptor expressing neurons; and 4) the striatal dopamine D2 receptor expressing neurons. Mice
will be assessed for general health, feeding, drinking, sleep, and potential seizures. In addition, working
memory, reference memory, reversal learning, motor coordination and motor learning will be examined. Brain
morphology and electrophysiology will be assessed. Levels of GABA, other PNPO-dependent
neurotransmitters, and their metabolites will be measured. The main goal of this R21 application is to test the
feasibility of such an approach. These models are potentially significant research tools for the research
community and may have a broad impact given the diverse distribution and functions of different GABAergic
projection neurons and interneurons.
摘要
GABA能神经元是成人神经系统的主要抑制性神经元。有不同的皮质
皮质下GABA能中间神经元和投射神经元具有不同的生理特性,
连接性和功能。然而,很少有研究能够调查特定的功能
通过干扰GABA选择性释放的亚类。我们提出了一种靶向GABA合成的方法
GABA能神经元的亚类。GAD活性需要辅因子吡哆醛-5-磷酸(PLP)。PLP
缺乏可以通过敲除PLP合成中的限速酶:吡哆醇-5-磷酸来实现
氧化酶(PNPO)。此外,PLP缺乏症可以通过全身应用PLP来挽救。因此,我们
建议建立细胞类型特异性PNPO缺乏症小鼠模型。我们将首先使用以下内容生成模型
在研究充分但高度不同的细胞类型中存在GABA缺陷,以测试我们方法的可行性:1)
Pv阳性的GABA能神经元;2)VIP阳性的GABA能神经元;3)纹状体
多巴胺D2受体阳性神经元;纹状体多巴胺D2受体阳性神经元。老鼠
将对一般健康、进食、饮水、睡眠和潜在的癫痫发作进行评估。此外,工作
将检查记忆、参考记忆、反转学习、运动协调和运动学习。脑区
将对形态学和电生理学进行评估。GABA和其他PNPO依赖的水平
神经递质及其代谢物将被测量。这个R21应用程序的主要目标是测试
这种方法的可行性。这些模型可能是研究的重要研究工具
社区和可能产生广泛的影响,因为不同的GABA能的不同的分布和功能
投射神经元和中间神经元。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Xiaoxi Zhuang其他文献
Xiaoxi Zhuang的其他文献
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{{ truncateString('Xiaoxi Zhuang', 18)}}的其他基金
Postsynaptic mechanisms underlying negative prediction error
负预测误差背后的突触后机制
- 批准号:
10682471 - 财政年份:2022
- 资助金额:
$ 23.73万 - 项目类别:
Postsynaptic mechanisms underlying negative prediction error
负预测误差背后的突触后机制
- 批准号:
10539883 - 财政年份:2022
- 资助金额:
$ 23.73万 - 项目类别:
Drosophila and mouse models of PNPO deficiency
PNPO 缺乏症的果蝇和小鼠模型
- 批准号:
10307547 - 财政年份:2019
- 资助金额:
$ 23.73万 - 项目类别:
Drosophila and mouse models of PNPO deficiency
PNPO 缺乏症的果蝇和小鼠模型
- 批准号:
9913752 - 财政年份:2019
- 资助金额:
$ 23.73万 - 项目类别:
Drosophila and mouse models of PNPO deficiency
PNPO 缺乏症的果蝇和小鼠模型
- 批准号:
10058294 - 财政年份:2019
- 资助金额:
$ 23.73万 - 项目类别:
Drosophila and mouse models of PNPO deficiency
PNPO 缺乏症的果蝇和小鼠模型
- 批准号:
10526424 - 财政年份:2019
- 资助金额:
$ 23.73万 - 项目类别:
RNA methylation in synaptic plasticity and drug-seeking
RNA甲基化在突触可塑性和药物寻找中的作用
- 批准号:
10159882 - 财政年份:2017
- 资助金额:
$ 23.73万 - 项目类别:
Genetic dissection of neural pathways for appetitive associative learning
食欲联想学习神经通路的遗传解剖
- 批准号:
8976537 - 财政年份:2015
- 资助金额:
$ 23.73万 - 项目类别:
Genetic dissection of neural pathways for appetitive associative learning
食欲联想学习神经通路的遗传解剖
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9066127 - 财政年份:2015
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Nicotine mitigates dopamine blockade-induced aberrant plasticity and learning
尼古丁减轻多巴胺阻断引起的异常可塑性和学习
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8633066 - 财政年份:2013
- 资助金额:
$ 23.73万 - 项目类别:
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