title: Changes in mGlu5 receptor-dependent synaptic plasticity and coupling to homer proteins in the hippocampus of Ube3A hemizygous mice modeling angelman syndrome.
abstract: 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 Ube3A(m-/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.
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Rome, Italy, Pharmacology of Synaptic Plasticity Unit, European Brain Research Institute, 00143 Rome, Italy, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, 86077 Pozzilli, Italy, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy, Institute of Cell Biology and Neurobiology, National Research Council, 00143 Rome, Italy, Institute of Neurological Sciences, National Research Council, 95126 Catania, Italy, and IRCCS Oasi Maria SS, 94018 Troina, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pignatelli
authors.forename: Sonia
authors.initials: S
authors.lastname: Piccinin
authors.forename: Gemma
authors.initials: G
authors.lastname: Molinaro
authors.forename: Luisa
authors.initials: L
authors.lastname: Di Menna
authors.forename: Barbara
authors.initials: B
authors.lastname: Riozzi
authors.forename: Milena
authors.initials: M
authors.lastname: Cannella
authors.forename: Marta
authors.initials: M
authors.lastname: Motolese
authors.forename: Gisella
authors.initials: G
authors.lastname: Vetere
authors.forename: Maria Vincenza
authors.initials: MV
authors.lastname: Catania
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.forename: Valeria
authors.initials: V
authors.lastname: Bruno
mesh_terms: D017204:Angelman Syndrome / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D057898:Hemizygote; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D000072233:Homer Scaffolding Proteins; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D000072233:Homer Scaffolding Proteins; D007166:Immunosuppressive Agents; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D008734:Methoxyhydroxyphenylglycol; C121465:6-methyl-2-(phenylethynyl)pyridine; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases; D020929:Mitogen-Activated Protein Kinase Kinases; C010117:3,4-dihydroxyphenylglycol; D020123:Sirolimus
keywords: Angelman syndrome; Homer proteins; LTD; hippocampus; metabotropic glutamate receptors