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BAI1 regulates spatial learning and synaptic plasticity in the hippocampus. 2015

Dan Zhu, and Chenchen Li, and Andrew M Swanson, and Rosa M Villalba, and Jidong Guo, and Zhaobin Zhang, and Shannon Matheny, and Tatsuro Murakami, and Jason R Stephenson, and Sarah Daniel, and Masaki Fukata, and Randy A Hall, and Jeffrey J Olson, and Gretchen N Neigh, and Yoland Smith, and Donald G Rainnie, and Erwin G Van Meir

Synaptic plasticity is the ability of synapses to modulate the strength of neuronal connections; however, the molecular factors that regulate this feature are incompletely understood. Here, we demonstrated that mice lacking brain-specific angiogenesis inhibitor 1 (BAI1) have severe deficits in hippocampus-dependent spatial learning and memory that are accompanied by enhanced long-term potentiation (LTP), impaired long-term depression (LTD), and a thinning of the postsynaptic density (PSD) at hippocampal synapses. We showed that compared with WT animals, mice lacking Bai1 exhibit reduced protein levels of the canonical PSD component PSD-95 in the brain, which stems from protein destabilization. We determined that BAI1 prevents PSD-95 polyubiquitination and degradation through an interaction with murine double minute 2 (MDM2), the E3 ubiquitin ligase that regulates PSD-95 stability. Restoration of PSD-95 expression in hippocampal neurons in BAI1-deficient mice by viral gene therapy was sufficient to compensate for Bai1 loss and rescued deficits in synaptic plasticity. Together, our results reveal that interaction of BAI1 with MDM2 in the brain modulates PSD-95 levels and thereby regulates synaptic plasticity. Moreover, these results suggest that targeting this pathway has therapeutic potential for a variety of neurological disorders.

UI MeSH Term Description Entries
D007859 Learning Disabilities Conditions characterized by a significant discrepancy between an individual's perceived level of intellect and their ability to acquire new language and other cognitive skills. These may result from organic or psychological conditions. Relatively common subtypes include DYSLEXIA, DYSCALCULIA, and DYSGRAPHIA. Adolescent Learning Disabilities,Adult Learning Disabilities,Child Learning Disabilities,Developmental Academic Disability,Developmental Academic Disorder,Developmental Disabilities of Scholastic Skills,Learning Disabilities, Adolescent,Learning Disabilities, Child,Learning Disorders,Academic Disorder, Developmental,Adult Learning Disorders,Developmental Disorders of Scholastic Skills,Learning Disorders, Adult,Learning Disturbance,Scholastic Skills Development Disorders,Academic Disabilities, Developmental,Academic Disability, Developmental,Academic Disorders, Developmental,Adolescent Learning Disability,Adult Learning Disability,Adult Learning Disorder,Child Learning Disability,Developmental Academic Disabilities,Developmental Academic Disorders,Disabilities, Adolescent Learning,Disabilities, Adult Learning,Disabilities, Child Learning,Disabilities, Developmental Academic,Disabilities, Learning,Disability, Adolescent Learning,Disability, Adult Learning,Disability, Child Learning,Disability, Developmental Academic,Disability, Learning,Disorder, Learning,Disorders, Adult Learning,Disorders, Learning,Disturbance, Learning,Disturbances, Learning,Learning Disabilities, Adult,Learning Disability,Learning Disability, Adolescent,Learning Disability, Adult,Learning Disability, Child,Learning Disorder,Learning Disorder, Adult,Learning Disturbances
D008565 Membrane Proteins Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. Cell Membrane Protein,Cell Membrane Proteins,Cell Surface Protein,Cell Surface Proteins,Integral Membrane Proteins,Membrane-Associated Protein,Surface Protein,Surface Proteins,Integral Membrane Protein,Membrane Protein,Membrane-Associated Proteins,Membrane Associated Protein,Membrane Associated Proteins,Membrane Protein, Cell,Membrane Protein, Integral,Membrane Proteins, Integral,Protein, Cell Membrane,Protein, Cell Surface,Protein, Integral Membrane,Protein, Membrane,Protein, Membrane-Associated,Protein, Surface,Proteins, Cell Membrane,Proteins, Cell Surface,Proteins, Integral Membrane,Proteins, Membrane,Proteins, Membrane-Associated,Proteins, Surface,Surface Protein, Cell
D008569 Memory Disorders Disturbances in registering an impression, in the retention of an acquired impression, or in the recall of an impression. Memory impairments are associated with DEMENTIA; CRANIOCEREBRAL TRAUMA; ENCEPHALITIS; ALCOHOLISM (see also ALCOHOL AMNESTIC DISORDER); SCHIZOPHRENIA; and other conditions. Memory Loss,Age-Related Memory Disorders,Memory Deficits,Memory Disorder, Semantic,Memory Disorder, Spatial,Memory Disorders, Age-Related,Retention Disorders, Cognitive,Semantic Memory Disorder,Spatial Memory Disorder,Age Related Memory Disorders,Age-Related Memory Disorder,Cognitive Retention Disorder,Cognitive Retention Disorders,Deficit, Memory,Deficits, Memory,Memory Deficit,Memory Disorder,Memory Disorder, Age-Related,Memory Disorders, Age Related,Memory Disorders, Semantic,Memory Disorders, Spatial,Memory Losses,Retention Disorder, Cognitive,Semantic Memory Disorders,Spatial Memory Disorders
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D009419 Nerve Tissue Proteins Proteins, Nerve Tissue,Tissue Proteins, Nerve
D009435 Synaptic Transmission The communication from a NEURON to a target (neuron, muscle, or secretory cell) across a SYNAPSE. In chemical synaptic transmission, the presynaptic neuron releases a NEUROTRANSMITTER that diffuses across the synaptic cleft and binds to specific synaptic receptors, activating them. The activated receptors modulate specific ion channels and/or second-messenger systems in the postsynaptic cell. In electrical synaptic transmission, electrical signals are communicated as an ionic current flow across ELECTRICAL SYNAPSES. Neural Transmission,Neurotransmission,Transmission, Neural,Transmission, Synaptic
D009473 Neuronal Plasticity The capacity of the NERVOUS SYSTEM to change its reactivity as the result of successive activations. Brain Plasticity,Plasticity, Neuronal,Axon Pruning,Axonal Pruning,Dendrite Arborization,Dendrite Pruning,Dendritic Arborization,Dendritic Pruning,Dendritic Remodeling,Neural Plasticity,Neurite Pruning,Neuronal Arborization,Neuronal Network Remodeling,Neuronal Pruning,Neuronal Remodeling,Neuroplasticity,Synaptic Plasticity,Synaptic Pruning,Arborization, Dendrite,Arborization, Dendritic,Arborization, Neuronal,Arborizations, Dendrite,Arborizations, Dendritic,Arborizations, Neuronal,Axon Prunings,Axonal Prunings,Brain Plasticities,Dendrite Arborizations,Dendrite Prunings,Dendritic Arborizations,Dendritic Prunings,Dendritic Remodelings,Network Remodeling, Neuronal,Network Remodelings, Neuronal,Neural Plasticities,Neurite Prunings,Neuronal Arborizations,Neuronal Network Remodelings,Neuronal Plasticities,Neuronal Prunings,Neuronal Remodelings,Neuroplasticities,Plasticities, Brain,Plasticities, Neural,Plasticities, Neuronal,Plasticities, Synaptic,Plasticity, Brain,Plasticity, Neural,Plasticity, Synaptic,Pruning, Axon,Pruning, Axonal,Pruning, Dendrite,Pruning, Dendritic,Pruning, Neurite,Pruning, Neuronal,Pruning, Synaptic,Prunings, Axon,Prunings, Axonal,Prunings, Dendrite,Prunings, Dendritic,Prunings, Neurite,Prunings, Neuronal,Prunings, Synaptic,Remodeling, Dendritic,Remodeling, Neuronal,Remodeling, Neuronal Network,Remodelings, Dendritic,Remodelings, Neuronal,Remodelings, Neuronal Network,Synaptic Plasticities,Synaptic Prunings
D009474 Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM. Nerve Cells,Cell, Nerve,Cells, Nerve,Nerve Cell,Neuron
D011499 Protein Processing, Post-Translational Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility. Amino Acid Modification, Post-Translational,Post-Translational Modification,Post-Translational Protein Modification,Posttranslational Modification,Protein Modification, Post-Translational,Amino Acid Modification, Posttranslational,Post-Translational Amino Acid Modification,Post-Translational Modifications,Post-Translational Protein Processing,Posttranslational Amino Acid Modification,Posttranslational Modifications,Posttranslational Protein Processing,Protein Processing, Post Translational,Protein Processing, Posttranslational,Amino Acid Modification, Post Translational,Modification, Post-Translational,Modification, Post-Translational Protein,Modification, Posttranslational,Modifications, Post-Translational,Modifications, Post-Translational Protein,Modifications, Posttranslational,Post Translational Amino Acid Modification,Post Translational Modification,Post Translational Modifications,Post Translational Protein Modification,Post Translational Protein Processing,Post-Translational Protein Modifications,Processing, Post-Translational Protein,Processing, Posttranslational Protein,Protein Modification, Post Translational,Protein Modifications, Post-Translational
D011993 Recombinant Fusion Proteins Recombinant proteins produced by the GENETIC TRANSLATION of fused genes formed by the combination of NUCLEIC ACID REGULATORY SEQUENCES of one or more genes with the protein coding sequences of one or more genes. Fusion Proteins, Recombinant,Recombinant Chimeric Protein,Recombinant Fusion Protein,Recombinant Hybrid Protein,Chimeric Proteins, Recombinant,Hybrid Proteins, Recombinant,Recombinant Chimeric Proteins,Recombinant Hybrid Proteins,Chimeric Protein, Recombinant,Fusion Protein, Recombinant,Hybrid Protein, Recombinant,Protein, Recombinant Chimeric,Protein, Recombinant Fusion,Protein, Recombinant Hybrid,Proteins, Recombinant Chimeric,Proteins, Recombinant Fusion,Proteins, Recombinant Hybrid

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