权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Neuroligin Function in vivo: Implications for Autism and Mental Retardation

Neuroligin 体内功能：对自闭症和智力迟钝的影响

基本信息

批准号：
8389578
负责人：
Craig M Powell
金额：
$ 37.3万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-23 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8389578
关键词：
Acute Address Affect Animal Model Attention Autistic Disorder Automobile Driving Behavior Behavioral Behavioral Paradigm Binding Cell Adhesion Molecules Clinical Data Deletion Mutation Disease Dose Equilibrium Excitatory Synapse Exhibits Family Fragile X Syndrome Frequencies Future Genes Genetic Genetic Models Hippocampus (Brain)Human Human Genetics Incidence Individual Inhibitory Synapse Integral Membrane Protein Knock-out Knockout Mice Learning Link Measurement Measures Mental Retardation Methods Modeling Mus Mutant Strains Mice Mutation N-Methyl-D-Aspartate Receptors N-Methylaspartate Neocortex Neurons Output Pathogenesis Patients Phenotype Physiological Picrotoxin Protein Binding Protocols documentation Publishing Rett Syndrome Role Slice Social Behavior Social Interaction Stimulus Synapses Synaptic plasticity Syndrome Testing To specify autism spectrum disorder base cognitive function follow-up gain of function human disease in vivo loss of function mutation member mouse model mutant neurobehavioral novel postsynaptic presynaptic research study synaptic function

项目摘要

Loss-of-function mutations in members of the neuroligin (NL) family of trans-synaptic cell adhesion molecules have been implicated in human autism and mental retardation. Animal models of autism have been severely limited, but these human genetic findings provide a novel path to develop bona fide mouse models of at least a subtype of human autism or mental retardation. NLs are postsynaptic transmembrane proteins that bind presynaptic beta-neurexins to induce formation of excitatory and inhibitory synapses and to control excitatory/inhibitory (E/I) synapse balance in cultured neurons. Alterations in E/I balance have been proposed as important in pathogenesis of autism and mental retardation. The precise role of NL in vivo and in neurobehavioral abnormalities in autism and mental retardation, however, remains to be determined. We will determine the role of neuroligin in vivo using electrophysiologic and behavioral characterization of NL knockout, human disease mutation knockin, and, in follow-up studies, conditional knockout mice. The driving hypothesis is that mice deficient in NL genes, or carrying known disease-linked mutations in NL, will exhibit behavioral differences consistent with those in human autism or mental retardation, and that these behavioral differences will be associated with specific abnormalities in E/I balance or synaptic function in cortical circuits in vivo. The following specific aims will be addressed: 1. To determine whether NL3 disease-linked mutation or deletion of NL3 result in autism and mental retardation-related behavioral abnormalities. 2. To determine whether deletion of NL3 or NL3 disease-linked mutations result in altered excitatory and inhibitory synaptic connectivity and function. 3. To determine whether deletion of NL3 or NL3 disease-linked mutations alter the threshold for inducing NMDA-receptor-dependent synaptic plasticity in the hippocampus.

跨突触细胞粘附分子神经配素（NL）家族成员的功能缺失突变与人类自闭症和智力迟钝有关。自闭症的动物模型已经严重有限，但这些人类遗传学发现提供了一种新的途径，以发展真正的小鼠模型，至少有一个人类自闭症或智力迟钝的亚型。 NLs是突触后跨膜蛋白，其结合突触前β-神经毒素以诱导突触后神经元的形成。兴奋性和抑制性突触，并控制兴奋性/抑制性（E/I）突触平衡，神经元E/I平衡的改变已被认为在自闭症和精神分裂症的发病机制中是重要的。迟钝NL在自闭症和精神分裂症患者体内和神经行为异常中的确切作用然而，延迟仍有待确定。我们将使用NL的电生理和行为特征来确定神经配素在体内的作用。敲除、人类疾病突变敲入，以及在后续研究中，条件性敲除小鼠。驱动假设是NL基因缺陷或携带已知NL疾病相关突变的小鼠将表现出行为差异与人类自闭症或精神发育迟滞一致，这些行为差异差异将与E/I平衡或皮层回路中突触功能的特定异常相关， vivo.将处理以下具体目标： 1.为了确定NL 3疾病相关突变或NL 3缺失是否导致自闭症和精神障碍，与发育迟缓有关的行为异常 2.为了确定NL 3的缺失或NL 3疾病相关突变是否导致兴奋性和兴奋性的改变，抑制性突触连接和功能。 3.为了确定NL 3缺失或NL 3疾病相关突变是否改变了诱导免疫应答的阈值，海马中NMDA受体依赖性突触可塑性。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity.

聚类自闭症：在26个小鼠模型中使用神经解剖学差异来深入了解异质性。

DOI：
10.1038/mp.2014.98
发表时间：
2015-02
期刊：
MOLECULAR PSYCHIATRY
影响因子：
11
作者：
Ellegood, J.;Anagnostou, E.;Babineau, B. A.;Crawley, J. N.;Lin, L.;Genestine, M.;DiCicco-Bloom, E.;Lai, J. K. Y.;Foster, J. A.;Penagarikano, O.;Geschwind, D. H.;Pacey, L. K.;Hampson, D. R.;Laliberte, C. L.;Mills, A. A.;Tam, E.;Osborne, L. R.;Kouser, M.;Espinosa-Becerra, F.;Xuan, Z.;Powell, C. M.;Raznahan, A.;Robins, D. M.;Nakai, N.;Nakatani, J.;Takumi, T.;van Eede, M. C.;Kerr, T. M.;Muller, C.;Blakely, R. D.;Veenstra-VanderWeele, J.;Henkelman, R. M.;Lerch, J. P.
通讯作者：
Lerch, J. P.

Increased Cortical Inhibition in Autism-Linked Neuroligin-3R451C Mice Is Due in Part to Loss of Endocannabinoid Signaling.

自闭症相关 Neuroligin-3R451C 小鼠的皮质抑制增加部分是由于内源性大麻素信号传导的丧失。

DOI：
10.1371/journal.pone.0140638
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Speed,HaleyE;Masiulis,Irene;Gibson,JayR;Powell,CraigM
通讯作者：
Powell,CraigM

Delayed reduction of hippocampal synaptic transmission and spines following exposure to repeated subclinical doses of organophosphorus pesticide in adult mice.

成年小鼠反复接触亚临床剂量的有机磷农药后，海马突触传递和棘的延迟减少。

DOI：
10.1093/toxsci/kfr253
发表时间：
2012
期刊：
Toxicological sciences : an official journal of the Society of Toxicology
影响因子：
0
作者：
Speed,HaleyE;Blaiss,CoryA;Kim,Ahleum;Haws,MichaelE;Melvin,NealR;Jennings,Michael;Eisch,AmeliaJ;Powell,CraigM
通讯作者：
Powell,CraigM

Spatial gene expression analysis of neuroanatomical differences in mouse models.

DOI：
10.1016/j.neuroimage.2017.08.065
发表时间：
2017-12
期刊：
NeuroImage
影响因子：
5.7
作者：
Fernandes DJ;Ellegood J;Askalan R;Blakely RD;Dicicco-Bloom E;Egan SE;Osborne LR;Powell CM;Raznahan A;Robins DM;Salter MW;Sengar AS;Veenstra-VanderWeele J;Henkelman RM;Lerch JP
通讯作者：
Lerch JP

A molecular mechanism for ibuprofen-mediated RhoA inhibition in neurons.

DOI：
10.1523/jneurosci.5045-09.2010
发表时间：
2010-01-20
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Dill J;Patel AR;Yang XL;Bachoo R;Powell CM;Li S
通讯作者：
Li S