title: Changes in the GRIP 1&2 scaffolding proteins in the cerebellum of the ataxic stargazer mouse.
abstract: Glutamate receptor-interacting proteins (GRIP1&2) and protein-interacting with C kinase-1 (PICK1) are synaptic scaffold proteins associated with the stabilization and recycling of synaptic GluA2-, 3- and 4c-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). PICK1-mediated phosphorylation of GluA serine880 uncouples GRIP1&2 leading to AMPAR endocytosis, important in mediating forms of synaptic plasticity underlying learning and memory. Ataxic and epileptic stargazer mice possess a mutation in the CACNG2 gene encoding the transmembrane AMPAR-regulatory protein (TARP)-γ2 (stargazin). TARPs are AMPAR-auxiliary subunits required for efficient AMPAR trafficking to synapses. Stargazin is abundantly expressed in the cerebellum and its loss results in severe deficits in AMPAR trafficking to cerebellar synapses, particularly at granule cell (GC) synapses, leading to the ataxic phenotype of stargazers. However, how the stargazin mutation impacts on the expression of other AMPAR-interacting scaffold proteins is unknown. This study shows a significant increase in GRIP1&2, but not PICK1, levels in whole tissue and synapse-enriched extracts from stargazer cerebella. Post-embedding immunogold-cytochemistry electron microscopy showed GRIP1&2 levels were unchanged at mossy fiber-GC synapses in stargazers, which are silent due to virtual total absence of synaptic and extrasynaptic GluA2/3-AMPARs. These results indicate that loss of synaptic AMPARs at this excitatory synapse does not affect GRIP1&2 expression within the postsynaptic region of mossy fiber-GC synapses. Interestingly, increased GRIP and reduced GluA2-AMPARexpression also occur in cerebella of autistic patients. Further research establishing the role of elevated cerebellar GRIP1&2 in stargazers may help identify common cellular mechanisms in the comorbid disorders ataxia, epilepsy and autism leading to more effective treatment strategies.
authors.affiliation: Department of Anatomy, Brain Health Research Centre, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors.forename: M
authors.initials: M
authors.lastname: Trotman
authors.affiliation: Department of Anatomy, Brain Health Research Centre, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors.forename: Z
authors.initials: Z
authors.lastname: Barad
authors.affiliation: Department of Anatomy, Brain Health Research Centre, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors.forename: D
authors.initials: D
authors.lastname: Guévremont
authors.affiliation: Department of Anatomy, Brain Health Research Centre, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
authors.forename: J
authors.initials: J
authors.lastname: Williams
authors.affiliation: Department of Anatomy, Brain Health Research Centre, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand. Electronic address: beulah.leitch@anatomy.otago.ac.nz.
authors.forename: B
authors.initials: B
authors.lastname: Leitch
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001259:Ataxia / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002531:Cerebellum / Q000378:metabolism* / Q000648:ultrastructure; D006624:Hippocampus / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113940:Cacng2 protein, mouse; D015220:Calcium Channels; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C491309:Grip1 protein, mouse; C485567:Grip2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C091822:Prkcabp protein, mouse
keywords: Autism; Cerebellum; GRIP1&2; Immunogold; PICK1; Stargazer