Changes in mGlu5 Receptor-Dependent Synaptic Plasticity and Coupling to Homer Proteins in the Hippocampus of Ube3A Hemizygous Mice Modeling Angelman Syndrome
Copyright policy )Changes in mGlu5 Receptor-Dependent Synaptic Plasticity and Coupling to Homer Proteins in the Hippocampus of Ube3A Hemizygous Mice Modeling Angelman Syndrome
Angelman syndrome (AS) is caused by the loss of Ube3A, an ubiquitin ligase that commits specific proteins to proteasomal degradation. How this defect causes autism and other pathological phenotypes associated with AS is unknown. Long-term depression (LTD) of excitatory synaptic transmission mediated by type 5 metabotropic glutamate (mGlu5) receptors was enhanced in hippocampal slices of Ube3Am−/p+mice, which model AS. No changes were found in NMDA-dependent LTD induced by low-frequency stimulation. mGlu5 receptor-dependent LTD in AS mice was sensitive to the protein synthesis inhibitor anisomycin, and relied on the same signaling pathways as in wild-type mice, e.g., the mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycine pathway, and protein tyrosine phosphatase. Neither the stimulation of MAPK and PI3K nor the increase in Arc (activity-regulated cytoskeleton-associated protein) levels in response to mGlu5 receptor activation were abnormal in hippocampal slices from AS mice compared with wild-type mice. mGlu5 receptor expression and mGlu1/5 receptor-mediated polyphosphoinositide hydrolysis were also unchanged in the hippocampus of AS mice. In contrast, AS mice showed a reduced expression of the short Homer protein isoform Homer 1a, and an increased coupling of mGlu5 receptors to Homer 1b/c proteins in the hippocampus. These findings support the link between Homer proteins and monogenic autism, and lay the groundwork for the use of mGlu5 receptor antagonists in AS.
Settore BIO/14 - FARMACOLOGIA, hippocampus, metabotropic glutamate receptors, Pyridines, Pyridine, Ubiquitin-Protein Ligases, Receptor, Metabotropic Glutamate 5, Mice, Transgenic, Mitogen-Activated Protein Kinase Kinase, In Vitro Techniques, Inbred C57BL, Hippocampus, Transgenic, Methoxyhydroxyphenylglycol, Immunosuppressive Agent, Mice, Homer Scaffolding Proteins, Excitatory Amino Acid Antagonist, Enzyme Inhibitor, Animals, Sirolimu, metabotropic glutamate receptor, Enzyme Inhibitors, Hemizygote, Mitogen-Activated Protein Kinase Kinases, Homer protein, hippocampu, Animal, In Vitro Technique, Long-Term Synaptic Depression, Angelman Syndrome; genetics/pathology, Animals, Carrier Proteins; genetics/metabolism, Disease Models; Animal, Enzyme Inhibitors; pharmacology, Excitatory Amino Acid Antagonists; pharmacology, Hemizygote, Hippocampus; pathology/physiopathology, Immunosuppressive Agents; pharmacology, Long-Term Synaptic Depression; physiology, Methoxyhydroxyphenylglycol; analogs /&/ derivatives/pharmacology, Mice, Mice; Inbred C57BL, Mice; Transgenic, Mitogen-Activated Protein Kinase Kinases; metabolism, Pyridines; pharmacology, Receptor; Metabotropic Glutamate 5; metabolism, Signal Transduction; drug effects/physiology, Sirolimus; pharmacology, Ubiquitin-Protein Ligases; genetics, Metabotropic Glutamate 5, Homer proteins, Mice, Inbred C57BL, Disease Models, Animal, Disease Models, Angelman syndrome, LTD, Angelman syndrome; Homer proteins; LTD; hippocampus; metabotropic glutamate receptors; Angelman Syndrome; Animals; Carrier Proteins; Disease Models, Animal; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Hemizygote; Hippocampus; Immunosuppressive Agents; In Vitro Techniques; Long-Term Synaptic Depression; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitogen-Activated Protein Kinase Kinases; Pyridines; Receptor, Metabotropic Glutamate 5; Signal Transduction; Sirolimus; Ubiquitin-Protein Ligases, Angelman Syndrome, Carrier Protein, Carrier Proteins, Excitatory Amino Acid Antagonists, Immunosuppressive Agents, Receptor, Signal Transduction
Settore BIO/14 - FARMACOLOGIA, hippocampus, metabotropic glutamate receptors, Pyridines, Pyridine, Ubiquitin-Protein Ligases, Receptor, Metabotropic Glutamate 5, Mice, Transgenic, Mitogen-Activated Protein Kinase Kinase, In Vitro Techniques, Inbred C57BL, Hippocampus, Transgenic, Methoxyhydroxyphenylglycol, Immunosuppressive Agent, Mice, Homer Scaffolding Proteins, Excitatory Amino Acid Antagonist, Enzyme Inhibitor, Animals, Sirolimu, metabotropic glutamate receptor, Enzyme Inhibitors, Hemizygote, Mitogen-Activated Protein Kinase Kinases, Homer protein, hippocampu, Animal, In Vitro Technique, Long-Term Synaptic Depression, Angelman Syndrome; genetics/pathology, Animals, Carrier Proteins; genetics/metabolism, Disease Models; Animal, Enzyme Inhibitors; pharmacology, Excitatory Amino Acid Antagonists; pharmacology, Hemizygote, Hippocampus; pathology/physiopathology, Immunosuppressive Agents; pharmacology, Long-Term Synaptic Depression; physiology, Methoxyhydroxyphenylglycol; analogs /&/ derivatives/pharmacology, Mice, Mice; Inbred C57BL, Mice; Transgenic, Mitogen-Activated Protein Kinase Kinases; metabolism, Pyridines; pharmacology, Receptor; Metabotropic Glutamate 5; metabolism, Signal Transduction; drug effects/physiology, Sirolimus; pharmacology, Ubiquitin-Protein Ligases; genetics, Metabotropic Glutamate 5, Homer proteins, Mice, Inbred C57BL, Disease Models, Animal, Disease Models, Angelman syndrome, LTD, Angelman syndrome; Homer proteins; LTD; hippocampus; metabotropic glutamate receptors; Angelman Syndrome; Animals; Carrier Proteins; Disease Models, Animal; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Hemizygote; Hippocampus; Immunosuppressive Agents; In Vitro Techniques; Long-Term Synaptic Depression; Methoxyhydroxyphenylglycol; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitogen-Activated Protein Kinase Kinases; Pyridines; Receptor, Metabotropic Glutamate 5; Signal Transduction; Sirolimus; Ubiquitin-Protein Ligases, Angelman Syndrome, Carrier Protein, Carrier Proteins, Excitatory Amino Acid Antagonists, Immunosuppressive Agents, Receptor, Signal Transduction
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