O-GlcNAcylation of AMPA receptor GluA2 is associated with a novel form of long-term depression at hippocampal synapses.
J Neurosci
; 34(1): 10-21, 2014 Jan 01.
Article
em En
| MEDLINE
| ID: mdl-24381264
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 ß-N-acetylglucosamine (O-GlcNAc) also occurs on serine residues. This, together with the high expression of the enzymes O-GlcNAc transferase (OGT) and ß-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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Acetilglucosaminidase
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Sinapses
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N-Acetilglucosaminiltransferases
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Receptores de AMPA
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Depressão Sináptica de Longo Prazo
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Hipocampo
Tipo de estudo:
Risk_factors_studies
Limite:
Aged80
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Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article