Impact of excitatory synapse maturation on synaptic plasticity and stability

兴奋性突触成熟对突触可塑性和稳定性的影响

• 批准号: 10450456
• 负责人: Michael James Higley
• 金额: $ 8.29万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450456
• 关键词: Address; Age; Alleles; Behavior; Binding; Binding Proteins; Biochemical; Biochemistry; Brain; Brain Diseases; Cell Surface Receptors; Cells; Chemosensitization; Cognitive deficits; Coupled; Cytoplasmic Tail; Data; Defect; Dendritic Spines; Development; Down-Regulation; Endocytosis; Excitatory Synapse; Exhibits; Frequencies; Gene Silencing; Genes; Genetic Epistasis; Glutamates; Growth Factor Receptors; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Head; Hippocampus (Brain); Homosynaptic Depression; Impairment; Integrin alpha3beta1; Intellectual functioning disability; Knock-out; Learning; Link; Long-Term Depression; Long-Term Potentiation; Measures; Mediating; Memory; Mental disorders; Methods; Mus; Mutate; N-Methyl-D-Aspartate Receptors; Nerve; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuroglia; Neurons; Noonan Syndrome; PTPN11 gene; Pattern; Phosphorylation; Phosphotransferases; Platelet-Derived Growth Factor beta Receptor; Population; Presynaptic Terminals; Probability; Protein Dephosphorylation; Protein Tyrosine Kinase; Proteins; Role; Signal Transduction; Synapses; Synaptic plasticity; Testing; Vertebral column; adhesion receptor; age related; base; emerging adult; experimental study; genetic approach; in vivo; in vivo imaging; individuals with autism spectrum disorder; mutant; novel; perinatal brain; postnatal; postsynaptic; postsynaptic neurons; preservation; receptor; sensory input; synaptic function

Immature excitatory synapses in the perinatal brain contain high release probability (Pr) presynaptic terminals coupled to postsynaptic specializations with GluN2B subunit-containing NMDA receptors (hi-Pr, hi-GluN2B synapses). For over two decades, we have known that these immature synapses mature in an activity- dependent manner to low-Pr, low-GluN2B synapses, but the mechanisms that coordinate this transition, why it occurs, and how it contributes to circuit plasticity and stability remain controversial and are fundamental unanswered questions. Addressing these issues will identify basic mechanisms that control synapse development and that may be disrupted in neurodevelopmental and psychiatric disorders. Disruption of the Arg/Abl2 kinase in mice yields a population of hi-Pr, hi-GluN2B synapses that persist into early adulthood. The persistence of these immature synapses drives a >40% net loss of hippocampal synapses between postnatal day (P) 21 and P42, and impairs synaptic plasticity and behavior. Building on these findings, we will identify new regulators of synapse maturation, and determine how they regulate synaptic plasticity and stability. In Aim 1, we will identify the cell surface receptors that activate Arg to coordinate the maturation from hi-Pr, hi- GluN2B synapses to low-Pr, low-GluN2B synapses. We provide preliminary data that integrin α3β1 adhesion receptor and platelet-derived growth factor receptor β (PDGFRβ) act upstream of Arg to control synapse function and stability. We will use selective gene inactivation in the pre- and postsynaptic neurons along with genetic epistasis and rescue experiments to address how and where these receptors interact with Arg and each other to regulate Pr and postsynaptic GluN2B levels. In Aim 2, we will elucidate how Arg mediates GluN2B downregulation at the synapse. Arg-mediated signaling is critical to downregulate GluN2B during maturation. We identified the SHP2 tyrosine phosphatase and the NMDAR-associated protein BRAG1, both mutated in intellectual disability, as likely functional links between Arg and developmental GluN2B downregulation. We will use biochemical, cell-based, and genetic approaches to test how Arg interacts with SHP2 and BRAG1 to downregulate GluN2B function. In Aim 3, we will characterize how immature and mature synapses differentially contribute to plasticity and stability. We will use patterned glutamate uncaging at single synapses to test whether hi-Pr, hi-GluN2B and low-Pr, low-GluN2B synapses have altered ability to undergo long-term potentiation (LTP) and long-term depression (LTD) in arg–/– mice. We will use in vivo imaging to examine how enlarged dendritic spines at hi- Pr, hi-GluN2B cortical synapses in arg–/– mice differ from normal spines in their plasticity and stability. Our studies will elucidate the mechanisms by which receptors act through Arg and its downstream targets to control Pr and NMDAR composition during synapse maturation. Disruption of these mechanisms may underlie the defects in synapse development, plasticity, and stability in intellectual disability and other brain disorders.

围产期大脑未成熟的兴奋性突触含有高释放概率（Pr）突触前末端

项目成果

Regulation of the NMDA receptor by its cytoplasmic domains: (How) is the tail wagging the dog?

• DOI: 10.1016/j.neuropharm.2021.108634
• 发表时间: 2021-09-01
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Ishchenko Y;Carrizales MG;Koleske AJ
• 通讯作者: Koleske AJ

Cortactin stabilization of actin requires actin-binding repeats and linker, is disrupted by specific substitutions, and is independent of nucleotide state.

肌动蛋白的 Cortactin 稳定性需要肌动蛋白结合重复序列和接头，会被特定取代破坏，并且与核苷酸状态无关。

• DOI: 10.1074/jbc.ra118.004068
• 发表时间: 2018
• 期刊: The Journal of biological chemistry
• 作者: Scherer,AlexanderN;Anand,NehaS;Koleske,AnthonyJ
• 通讯作者: Koleske,AnthonyJ

Measuring Cell-Edge Protrusion Dynamics during Spreading using Live-Cell Microscopy.

• DOI: 10.3791/63157
• 发表时间: 2021-11-01
• 期刊: Journal of visualized experiments : JoVE
• 作者: Lukic N;Saha T;Lapetina S;Gendler M;Lehmann G;Koleske AJ;Gil-Henn H
• 通讯作者: Gil-Henn H

Autoinhibition of the GEF activity of cytoskeletal regulatory protein Trio is disrupted in neurodevelopmental disorder-related genetic variants.

• DOI: 10.1016/j.jbc.2022.102361
• 发表时间: 2022-09
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Bircher, Josie E.;Corcoran, Ellen E.;Lam, TuKiet T.;Trnka, Michael J.;Koleske, Anthony J.
• 通讯作者: Koleske, Anthony J.

A Role for the Non-Receptor Tyrosine Kinase Abl2/Arg in Experimental Neuroinflammation.

非受体酪氨酸激酶 Abl2/Arg 在实验性神经炎症中的作用。

• DOI: 10.1007/s11481-018-9783-8
• 发表时间: 2018
• 期刊: Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
• 作者: Jacobsen,FrejaAksel;Scherer,AlexanderN;Mouritsen,Jeppe;Bragadóttir,Hera;ThomasBäckström,B;Sardar,Samra;Holmberg,Dan;Koleske,AnthonyJ;Andersson,Åsa
• 通讯作者: Andersson,Åsa