In vivo modulation of O-GlcNAc levels regulates hippocampal synaptic plasticity through interplay with phosphorylation.
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 (O-GlcNAc transferase) 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, a form of short term plasticity attributed to presynaptic mechanisms. Synapsin I and II are presynaptic proteins that increase synaptic vesicle 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 (cAMP-dependent protein kinase substrate site), serine 62/67 (Erk 1/2 (MAPK 1/2) substrate site), and serine 603 (calmodulin kinase II site). Activation-specific phosphorylation events on Erk 1/2 and calmodulin 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.
Tallent
Melanie K
MK
Department of Biochemistry and Molecular Biology and Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 and the Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
Varghis
Neal
N
Department of Biochemistry and Molecular Biology and Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 and the Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
Skorobogatko
Yuliya
Y
Department of Biochemistry and Molecular Biology and Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 and the Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
Hernandez-Cuebas
Lisa
L
Department of Biochemistry and Molecular Biology and Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 and the Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
Whelan
Kelly
K
Department of Biochemistry and Molecular Biology and Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 and the Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
Vocadlo
David J
DJ
Department of Biochemistry and Molecular Biology and Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 and the Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
Vosseller
Keith
K
Department of Biochemistry and Molecular Biology and Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 and the Department of Chemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada. Electronic address: keith.vosseller@drexelmed.edu.
D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D007858:Learning / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D016704:Synapsins / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism*
D016704:Synapsins; D017351:N-Acetylglucosaminyltransferases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000117:Acetylglucosamine