title: O-GlcNAcylation of AMPA receptor GluA2 is associated with a novel form of long-term depression at hippocampal synapses.
abstract: Serine phosphorylation of AMPA receptor (AMPAR) subunits GluA1 and GluA2 modulates AMPAR trafficking during long-term changes in strength of hippocampal excitatory transmission required for normal learning and memory. The post-translational addition and removal of O-linked β-N-acetylglucosamine (O-GlcNAc) also occurs on serine residues. This, together with the high expression of the enzymes O-GlcNAc transferase (OGT) and β-N-acetylglucosamindase (O-GlcNAcase), suggests a potential role for O-GlcNAcylation in modifying synaptic efficacy and cognition. Furthermore, because key synaptic proteins are O-GlcNAcylated, this modification may be as important to brain function as phosphorylation, yet its physiological significance remains unknown. We report that acutely increasing O-GlcNAcylation in Sprague Dawley rat hippocampal slices induces an NMDA receptor and protein kinase C-independent long-term depression (LTD) at hippocampal CA3-CA1 synapses (O-GcNAc LTD). This LTD requires AMPAR GluA2 subunits, which we demonstrate are O-GlcNAcylated. Increasing O-GlcNAcylation interferes with long-term potentiation, and in hippocampal behavioral assays, it prevents novel object recognition and placement without affecting contextual fear conditioning. Our findings provide evidence that O-GlcNAcylation dynamically modulates hippocampal synaptic function and learning and memory, and suggest that altered O-GlcNAc levels could underlie cognitive dysfunction in neurological diseases.
authors.affiliation: Department of Cell, Developmental and Integrative Biology, Department of Neurology, Department of Psychiatry and Behavioral Neurobiology, and Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Erica W
authors.initials: EW
authors.lastname: Taylor
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Amy R
authors.initials: AR
authors.lastname: Nelson
authors.forename: Teruko M
authors.initials: TM
authors.lastname: Bredemann
authors.forename: Kyle B
authors.initials: KB
authors.lastname: Fraser
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Clinton
authors.forename: Rosemary
authors.initials: R
authors.lastname: Puckett
authors.forename: Richard B
authors.initials: RB
authors.lastname: Marchase
authors.forename: John C
authors.initials: JC
authors.lastname: Chatham
authors.forename: Lori L
authors.initials: LL
authors.lastname: McMahon
mesh_terms: D000118:Acetylglucosaminidase / Q000378:metabolism*; D000215:Acylation / Q000502:physiology; D000369:Aged, 80 and over; D000818:Animals; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008297:Male; D057507:Mice, 129 Strain; D008817:Mice, Mutant Strains; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
chemical_list: D018091:Receptors, AMPA; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D000118:Acetylglucosaminidase; C104722:glutamate receptor ionotropic, AMPA 2
keywords: LTD; LTP; O-GlcNAc; depression; hippocampus; synaptic transmission