Abstract Title:

In vivo modulation of O-GlcNAc levels regulates hippocampal synaptic plasticity through interplay with phosphorylation.

Abstract Source:

J Biol Chem. 2008 Nov 11. [Epub ahead of print] PMID: 19004831

Abstract Author(s):

Melanie K Tallent, Neal Varghis, Yuliya Skorobogatko, Lisa Hernandez-Cuebas, Kelly Whelan, David J Vocadlo, Keith Vosseller


O-linked N-acetylglucosamine (O-GlcNAc) is a cytosolic and nuclear carbohydrate post-translational modification most abundant in brain. We recently reported uniquely extensive O-GlcNAc modification of proteins that function in synaptic vesicle release and post-synaptic signal transduction. Here, we examined potential roles for O-GlcNAc in mouse hippocampal synaptic transmission and plasticity. O-GlcNAc modifications and the enzyme catalyzing their addition (OGT) were enriched in hippocampal synaptosomes. Pharmacological elevation or reduction of O-GlcNAc levels had no effect on Schaffer collateral CA1 basal hippocampal synaptic transmission. However, in vivo elevation of O-GlcNAc levels enhanced long term potentiation (LTP), an electrophysiological correlate to some forms of learning/memory. Reciprocally, pharmacological reduction of O-GlcNAc levels blocked LTP. Additionally, elevated O-GlcNAc led to reduced paired-pulse facilitation (PPF), a form of short-term plasticity attributed to presynaptic mechanisms. Synapsin I and II are presynaptic proteins that increase synaptic vesicle (SV) availability for release when phosphorylated, thus contributing to hippocampal synaptic plasticity. Synapsins are among the most extensively O-GlcNAc modified proteins known. Elevating O-GlcNAc levels increased phosphorylation of synapsin I/II at serine 9 (PKA substrate site), serine 62/67 (Erk 1/2 [MAPK 1/2] substrate site), and serine 603 (Cam Kinase II site). Activation specific phosphorylation events on Erk 1/2 and Cam Kinase II, two proteins required for CA1 hippocampal LTP establishment, were increased in response to elevation of O-GlcNAc levels. Thus, O-GlcNAc is a novel regulatory signaling component of excitatory synapses, with specific roles in synaptic plasticity that involve interplay with phosphorylation.

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