Changes in mGlu5 receptor-dependent synaptic plasticity and coupling to homer proteins in the hippocampus of Ube3A hemizygous mice modeling angelman syndrome

Marco Pignatelli, Sonia Piccinin, Gemma Molinaro, Luisa Di Menna, Barbara Riozzi, Milena Cannella, Marta Motolese, Gisella Vetere, Maria Vincenza Catania, Giuseppe Battaglia, Ferdinando Nicoletti, Robert Nisticò, Valeria Bruno

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

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 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 Homerprotein isoform Homer1a, and an increased coupling of mGlu5 receptors to Homer1b/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.

Original languageEnglish
Pages (from-to)4558-4566
Number of pages9
JournalJournal of Neuroscience
Volume34
Issue number13
DOIs
StatePublished - 2014

Keywords

  • Angelman syndrome
  • Hippocampus
  • Homer proteins
  • LTD
  • Metabotropic glutamate receptors

Fingerprint Dive into the research topics of 'Changes in mGlu5 receptor-dependent synaptic plasticity and coupling to homer proteins in the hippocampus of Ube3A hemizygous mice modeling angelman syndrome'. Together they form a unique fingerprint.

Cite this