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 mϪ/pϩ 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.

Oligomers of Amyloid β Prevent Physiological Activation of the Cellular Prion Protein-Metabotropic Glutamate Receptor 5 Complex by Glutamate in Alzheimer Disease

“…We conclude that physiologically fluctuating levels of glutamate might be unable to modify the interaction between mGluR5 and intracellular signaling mediators in a pathophysiological A␤o-dependent disease state. Similar pathophysiological association states between mGluRs and Homer scaffolding proteins have been proposed in the context of several neurological diseases, including fragile X syndrome and Angelman syndrome (48,49). Our data suggests that preventing A␤o-induced activation of the PrP C -mGluR5 signaling complex has potential clinical implications for Alzheimer disease.…”

Role of Spinophilin in Group I Metabotropic Glutamate Receptor Endocytosis, Signaling, and Synaptic Plasticity

“…This probably occurs as a consequence of the fact that DHPG-induced LTD in the Schaffer collateral/CA1 synapse is induced by activation of postsynaptic mGluR5 receptors but has been shown also by others to be associated with an increase of paired pulse ratio, indicating a decrease in transmitter release probability during long-term depression (41). Accordingly, we observed an increase of PPR in wild-type mice after DHPG during LTD expression but not in knock-out mice after DHPG application.…”

“…However, there is limited evidence to suggest that ␤-arrestins interact with mGluRs to regulate either their endocytosis or signaling, with the majority of studies suggesting that ␤-arrestins play no role in regulating the activity of mGluRs (28). Nevertheless, spinophilin has been demonstrated to bind directly to GRK2 and G␤5, and GRK2 plays a central role in regulating Group I mGluR desensitization and internalization (34,41). Thus, it is possible that spinophilin interactions with Group I mGluRs may regulate GRK2 interactions with Group I mGluRs, thereby contributing to the regulation of their endocytosis and signaling.…”

Impaired adult hippocampal neurogenesis and its partial reversal by chronic treatment of fluoxetine in a mouse model of Angelman syndrome

“…Impaired hippocampal neurogenesis could conceivably compromise hippocampal function and amplify cognitive defect seen in AS mice. So far, several contributing factor have been identified that could lead to learning and memory impairment in AS mice, which includes aberrant activity of hippocampal CAMKIIa [13,14], enhanced neuregulin-Erb4 signalling [33], defect in experience-dependent synaptic plasticity [34,35] etc.…”