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Article: Presynaptic inhibition of glutamate release by neuropeptides: use-dependent synaptic modification.

Tallent, Melanie K

Results and problems in cell differentiation

2008 Volume 44, Page(s) 177–200

Abstract: Neuropeptides are signaling molecules that interact with G-protein coupled receptors located both pre- and postsynaptically. Presynaptically, these receptors are localized in axons and terminals away from presynaptic specializations. Neuropeptides are ... ...

Abstract	Neuropeptides are signaling molecules that interact with G-protein coupled receptors located both pre- and postsynaptically. Presynaptically, these receptors are localized in axons and terminals away from presynaptic specializations. Neuropeptides are stored in dense core vesicles that are distinct from the clear synaptic vesicles containing classic neurotransmitters such as glutamate and GABA. Because they require a stronger Ca(2+) signal than synaptic vesicles, dense core vesicles do not release neuropeptides with single action potentials but rather require high-frequency trains. Thus, neuropeptides only modulate strongly stimulated synapses, providing negative or positive feedback. Many neuropeptides have been found to inhibit glutamate release from presynaptic terminals, and the major mechanism is likely direct interaction of betagamma G-protein subunits with presynaptic proteins such as SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor). The use of mouse genetic models and specific receptor antagonists are beginning to unravel the function of inhibitory neuropeptides. The opioid receptors kappa and mu, which are activated by endogenous opioid peptides such as dynorphin, enkephalin, and possibly the endomorphins, are important in modulating pain transmission. Dynorphin, nociceptin/orphanin FQ, and somatostatin and its related peptide cortistatin appear to play a role in modulation of learning and memory. Neuropeptide Y has important functions in ingestive behavior and also in entraining circadian rhythms. The existence of neuropeptides greatly expands the computational ability of the brain by providing additional levels of modulation.
MeSH term(s)	Animals ; Behavior, Animal/physiology ; Calcium Signaling/physiology ; Excitatory Postsynaptic Potentials/physiology ; Mice ; Neuropeptides/physiology ; Presynaptic Terminals/physiology ; Receptors, Neuropeptide/physiology ; SNARE Proteins/metabolism ; Synaptic Transmission/physiology
Chemical Substances	Neuropeptides ; Receptors, Neuropeptide ; SNARE Proteins
Language	English
Publishing date	2008
Publishing country	Germany
Document type	Journal Article ; Review
ISSN	0080-1844
ISSN	0080-1844
DOI	10.1007/400_2007_037
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Article: Somatostatin in the dentate gyrus.

Tallent, Melanie K

Progress in brain research

2007 Volume 163, Page(s) 265–284

Abstract: The neuropeptide somatostatin (SST) is expressed in a discrete population of interneurons in the dentate gyrus. These interneurons have their soma in the hilus and project to the outer molecular layer onto dendrites of dentate granule cells, adjacent to ... ...

Abstract	The neuropeptide somatostatin (SST) is expressed in a discrete population of interneurons in the dentate gyrus. These interneurons have their soma in the hilus and project to the outer molecular layer onto dendrites of dentate granule cells, adjacent to perforant path input. SST-containing interneurons are very sensitive to excitotoxicty, and thus are vulnerable to a variety of neurological diseases and insults, including epilepsy, Alzheimer's disease, traumatic brain injury, and ischemia. The SST gene contains a prototypical cyclic AMP response element (CRE) site. Such a regulatory site confers activity-dependence to the gene, such that it is turned on when neuronal activity is high. Thus SST expression is increased by pathological conditions such as seizures and by natural stimulation such as environmental enrichment. SST may play an important role in cognition by modulating the response of neurons to synaptic input. In the dentate, SST and the related peptide cortistatin (CST) reduce the likelihood of generating long-term potentiation, a cellular process involved in learning and memory. Thus these neuropeptides would increase the threshold of input required for acquisition of new memories, increasing "signal to noise" to filter out irrelevant environmental cues. The major mechanism through which SST inhibits LTP is likely through inhibition of voltage-gated Ca(2+) channels on dentate granule cell dendrites. Transgenic overexpression of CST in the dentate leads to profound deficits in spatial learning and memory, validating its role in cognitive processing. A reduction of synaptic potentiation by SST and CST in dentate may also contribute to the well-characterized antiepileptic properties of these neuropeptides. Thus SST and CST are important neuromodulators in the dentate gyrus, and disruption of this signaling system may have major impact on hippocampal function.
MeSH term(s)	Animals ; Dentate Gyrus/cytology ; Dentate Gyrus/metabolism ; Humans ; Interneurons/metabolism ; Interneurons/physiology ; Somatostatin/metabolism
Chemical Substances	Somatostatin (51110-01-1)
Language	English
Publishing date	2007
Publishing country	Netherlands
Document type	Journal Article ; Review
ISSN	0079-6123
ISSN	0079-6123
DOI	10.1016/S0079-6123(07)63016-7
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Article ; Online: AMPA GluA1-flip targeted oligonucleotide therapy reduces neonatal seizures and hyperexcitability.

Lykens, Nicole M / Coughlin, David J / Reddi, Jyoti M / Lutz, Gordon J / Tallent, Melanie K

PloS one

2017 Volume 12, Issue 2, Page(s) e0171538

Abstract: Glutamate-activated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) mediate the majority of excitatory neurotransmission in brain and thus are major drug targets for diseases associated with hyperexcitability or neurotoxicity. ... ...

Abstract	Glutamate-activated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) mediate the majority of excitatory neurotransmission in brain and thus are major drug targets for diseases associated with hyperexcitability or neurotoxicity. Due to the critical nature of AMPA-Rs in normal brain function, typical AMPA-R antagonists have deleterious effects on cognition and motor function, highlighting the need for more precise modulators. A dramatic increase in the flip isoform of alternatively spliced AMPA-R GluA1 subunits occurs post-seizure in humans and animal models. GluA1-flip produces higher gain AMPA channels than GluA1-flop, increasing network excitability and seizure susceptibility. Splice modulating oligonucleotides (SMOs) bind to pre-mRNA to influence alternative splicing, a strategy that can be exploited to develop more selective drugs across therapeutic areas. We developed a novel SMO, GR1, which potently and specifically decreased GluA1-flip expression throughout the brain of neonatal mice lasting at least 60 days after single intracerebroventricular injection. GR1 treatment reduced AMPA-R mediated excitatory postsynaptic currents at hippocampal CA1 synapses, without affecting long-term potentiation or long-term depression, cellular models of memory, or impairing GluA1-dependent cognition or motor function in mice. Importantly, GR1 demonstrated anti-seizure properties and reduced post-seizure hyperexcitability in neonatal mice, highlighting its drug candidate potential for treating epilepsies and other neurological diseases involving network hyperexcitability.
MeSH term(s)	Alternative Splicing ; Animals ; Animals, Newborn ; Base Sequence ; Cognition ; Disease Models, Animal ; Disease Susceptibility ; Female ; Hippocampus/metabolism ; Hippocampus/physiopathology ; Male ; Mice ; Motor Activity ; Oligonucleotides/administration & dosage ; Oligonucleotides/chemistry ; Pyramidal Cells/metabolism ; Receptors, AMPA/genetics ; Seizures/genetics ; Seizures/physiopathology ; Seizures/therapy ; Synaptic Transmission/genetics
Chemical Substances	Oligonucleotides ; Receptors, AMPA ; glutamate receptor ionotropic, AMPA 1 (TFZ3H25BS1)
Language	English
Publishing date	2017-02-08
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0171538
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Article ; Online: Somatostatin: an endogenous antiepileptic.

Tallent, Melanie K / Qiu, Cuie

Molecular and cellular endocrinology

2007 Volume 286, Issue 1-2, Page(s) 96–103

Abstract: The neuropeptide somatostatin (SST) is highly expressed in brain regions associated with seizures. In hippocampus, SST expression and release is regulated by seizures, and SST-containing neurons within the hilus of the dentate gyrus are sensitive to ... ...

Abstract	The neuropeptide somatostatin (SST) is highly expressed in brain regions associated with seizures. In hippocampus, SST expression and release is regulated by seizures, and SST-containing neurons within the hilus of the dentate gyrus are sensitive to seizure-induced death. In vivo and in vitro studies suggest that the loss of SST function in the dentate could contribute to epileptogenesis and seizure susceptibility. SST also has inhibitory actions in the CA1 and CA3 hippocampus indicating this peptide is an important homeostatic regulator throughout the hippocampus. In vivo studies show SST has robust antiepileptic properties with the major site of action being hippocampus. In rodents, somatostatin receptor subtype 2 (SST(2)) and SST(4) appear to mediate the majority of the antiepileptic actions of SST, with SST(2) predominate in rat and SST(4) in mouse. Thus SST receptors may be appropriate targets for new antiepileptic drugs (AEDs), although validation in human tissue is lacking.
MeSH term(s)	Animals ; Anticonvulsants/therapeutic use ; Dentate Gyrus/drug effects ; Dentate Gyrus/metabolism ; Dentate Gyrus/pathology ; Epilepsy/drug therapy ; Epilepsy/metabolism ; Epilepsy/pathology ; Hippocampus/drug effects ; Hippocampus/metabolism ; Hippocampus/pathology ; Humans ; Neurons/drug effects ; Neurons/metabolism ; Neurons/pathology ; Receptors, Somatostatin/agonists ; Receptors, Somatostatin/metabolism ; Seizures/drug therapy ; Seizures/metabolism ; Seizures/pathology ; Somatostatin/physiology
Chemical Substances	Anticonvulsants ; Receptors, Somatostatin ; somatostatin receptor subtype-4 ; Somatostatin (51110-01-1) ; somatostatin receptor 2 (D73QL0OMU2)
Language	English
Publishing date	2007-12-14
Publishing country	Ireland
Document type	Journal Article ; Review
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2007.12.004
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Article: Interneuron Diversity series: Interneuronal neuropeptides--endogenous regulators of neuronal excitability.

Baraban, Scott C / Tallent, Melanie K

Trends in neurosciences

2004 Volume 27, Issue 3, Page(s) 135–142

Abstract: Interneurons are often classified according to neuropeptide content. However, it is becoming increasingly clear that neuropeptides are more than convenient neurochemical markers and can act as important modulators of neuronal activity. Recent advances in ...

Abstract	Interneurons are often classified according to neuropeptide content. However, it is becoming increasingly clear that neuropeptides are more than convenient neurochemical markers and can act as important modulators of neuronal activity. Recent advances in understanding neuropeptide release and physiological actions suggest that the interneuronal system of neuropeptides is crucial for maintaining appropriate brain function under normal and pathophysiological conditions. In particular, interneuronal neuropeptides appear to play roles in cognition and as endogenous anti-epileptic agents. This article describes current understanding of the conditions under which neuropeptides are released from interneurons, their specific effects on neuronal excitability and synaptic transmission, and the consequences of their loss of function.
MeSH term(s)	Animals ; Brain/physiology ; Brain Diseases/physiopathology ; Epilepsy/metabolism ; Epilepsy/physiopathology ; Interneurons/classification ; Interneurons/physiology ; Neural Inhibition ; Neuropeptide Y/physiology ; Neuropeptides/physiology ; Somatostatin/physiology ; Synaptic Transmission/physiology
Chemical Substances	Neuropeptide Y ; Neuropeptides ; Somatostatin (51110-01-1)
Language	English
Publishing date	2004-03
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	282488-7
ISSN	1878-108X ; 0166-2236 ; 0378-5912
ISSN (online)	1878-108X
ISSN	0166-2236 ; 0378-5912
DOI	10.1016/j.tins.2004.01.008
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Article ; Online: AMPA GluA1-flip targeted oligonucleotide therapy reduces neonatal seizures and hyperexcitability.

Nicole M Lykens / David J Coughlin / Jyoti M Reddi / Gordon J Lutz / Melanie K Tallent

PLoS ONE, Vol 12, Iss 2, p e

2017 Volume 0171538

Abstract	Glutamate-activated α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) mediate the majority of excitatory neurotransmission in brain and thus are major drug targets for diseases associated with hyperexcitability or neurotoxicity. Due to the critical nature of AMPA-Rs in normal brain function, typical AMPA-R antagonists have deleterious effects on cognition and motor function, highlighting the need for more precise modulators. A dramatic increase in the flip isoform of alternatively spliced AMPA-R GluA1 subunits occurs post-seizure in humans and animal models. GluA1-flip produces higher gain AMPA channels than GluA1-flop, increasing network excitability and seizure susceptibility. Splice modulating oligonucleotides (SMOs) bind to pre-mRNA to influence alternative splicing, a strategy that can be exploited to develop more selective drugs across therapeutic areas. We developed a novel SMO, GR1, which potently and specifically decreased GluA1-flip expression throughout the brain of neonatal mice lasting at least 60 days after single intracerebroventricular injection. GR1 treatment reduced AMPA-R mediated excitatory postsynaptic currents at hippocampal CA1 synapses, without affecting long-term potentiation or long-term depression, cellular models of memory, or impairing GluA1-dependent cognition or motor function in mice. Importantly, GR1 demonstrated anti-seizure properties and reduced post-seizure hyperexcitability in neonatal mice, highlighting its drug candidate potential for treating epilepsies and other neurological diseases involving network hyperexcitability.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2017-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article: K+ M-current regulates the transition to seizures in immature and adult hippocampus.

Qiu, Cuie / Johnson, Brian N / Tallent, Melanie K

Epilepsia

2007 Volume 48, Issue 11, Page(s) 2047–2058

Abstract: Purpose: Loss-of-function mutations in Kv7.2 or Kv7.3 K(+) channel subunits underlies ... the neonatal epilepsy benign familial neonatal convulsions (BFNC). These two subunits interact to form a functional K ... channel that underlies the M-current (I(M)), a voltage-dependent noninactivating K(+) current. In BFNC ...

Abstract	Purpose: Loss-of-function mutations in Kv7.2 or Kv7.3 K(+) channel subunits underlies the neonatal epilepsy benign familial neonatal convulsions (BFNC). These two subunits interact to form a functional K(+) channel that underlies the M-current (I(M)), a voltage-dependent noninactivating K(+) current. In BFNC, seizures begin shortly after birth, and spontaneously remit in the first few months of life. The nature of this window of vulnerability is unclear. We address this issue using a hippocampal slice model, to study the effects of I(M) blockade or augmentation on epileptiform activity. Methods: We used the Mg(+)(+)-free seizure model in adult and immature (P8-P15) acute rat hippocampal slices. We recorded from both CA1 and CA3 regions using extracellular and intracellular methods. Results: When M-channels are blocked pharmacologically, the transition from interictal to ictal bursting becomes much more likely, especially in immature brain. We also show augmentation of I(M) is effective in stopping ictal events in immature brain, at the developmental age that approximates a human newborn in cortical development. I(M) appears to counter the sustained N-methyl-D-aspartate (NMDA) receptor-mediated depolarizations needed to trigger an ictal event. The increased likelihood of ictal bursting by I(M) blockade is not shared by other selective K(+) channel blockers that increase hippocampal excitability. Conclusions: Voltage-dependent M-channels are activated during interictal bursts and contribute to burst termination. When these channels are compromised, interictal burst duration becomes sufficient to trigger the sustained depolarizations that underlie ictal bursts. This transition to ictal bursts upon I(M) blockade is especially likely to occur in immature hippocampus. This selective function of M-channels likely contributes to the transient window of vulnerability to seizures that occurs with BFNC.
MeSH term(s)	Action Potentials/drug effects ; Action Potentials/genetics ; Action Potentials/physiology ; Animals ; Anticonvulsants/pharmacology ; Carbamates/pharmacology ; Disease Models, Animal ; Epilepsy, Benign Neonatal/genetics ; Epilepsy, Benign Neonatal/physiopathology ; Hippocampus/drug effects ; Hippocampus/growth & development ; Hippocampus/physiopathology ; Humans ; Indoles/pharmacology ; Male ; Mutation/genetics ; Phenylenediamines/pharmacology ; Potassium Channel Blockers/pharmacology ; Potassium Channels, Voltage-Gated/antagonists & inhibitors ; Potassium Channels, Voltage-Gated/genetics ; Potassium Channels, Voltage-Gated/physiology ; Pyridines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/drug effects ; Receptors, N-Methyl-D-Aspartate/physiology ; Seizures/genetics ; Seizures/physiopathology
Chemical Substances	Anticonvulsants ; Carbamates ; Indoles ; Phenylenediamines ; Potassium Channel Blockers ; Potassium Channels, Voltage-Gated ; Pyridines ; Receptors, N-Methyl-D-Aspartate ; ezogabine (12G01I6BBU) ; linopirdine (I5TB3NZ94T)
Language	English
Publishing date	2007-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	216382-2
ISSN	1528-1167 ; 0013-9580
ISSN (online)	1528-1167
ISSN	0013-9580
DOI	10.1111/j.1528-1167.2007.01193.x
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Article: Somatostatin depresses long-term potentiation and Ca2+ signaling in mouse dentate gyrus.

Baratta, Michael V / Lamp, Tyra / Tallent, Melanie K

Journal of neurophysiology

2002 Volume 88, Issue 6, Page(s) 3078–3086

Abstract: ... Unlike findings in the CA1 hippocampus, we observed no postsynaptic actions on K(+) currents. Instead ...

Abstract	The selective loss of somatostatin (SST)-containing interneurons from the hilus of the dentate gyrus is a hallmark of epileptic hippocampus. The functional consequence of this loss, including its contribution to postseizure hyperexcitability, remains unclear. We address this issue by characterizing the actions of SST in mouse dentate gyrus using electrophysiological techniques. Although the majority of dentate SST receptors are located in the outer molecular layer adjacent to lateral perforant path (LPP) synapses, we found no consistent action of SST on standard synaptic responses generated at these synapses. However, when SST was present during application of high-frequency trains that normally generate long-term potentiation (LTP), the induction of LTP was impaired. SST did not alter the maintenance of LTP when applied after its induction. To examine the mechanism by which SST inhibits LTP, we recorded from dentate granule cells and examined the actions of this neuropeptide on synaptic transmission and postsynaptic currents. Unlike findings in the CA1 hippocampus, we observed no postsynaptic actions on K(+) currents. Instead, SST inhibited Ca(2+)/Ba(2+) spikes evoked by depolarization. This inhibition was dependent on N-type Ca(2+)currents. Blocking these currents also blocked LTP, suggesting a mechanism through which SST may inhibit LTP. Our results indicate that SST reduction of dendritic Ca(2+) through N-type Ca(2+) channels may contribute to modulation of synaptic plasticity at LPP synapses. Therefore the loss of SST function postseizure could result in abnormal synaptic potentiation that contributes to epileptogenesis.
MeSH term(s)	Action Potentials/drug effects ; Animals ; Calcium/physiology ; Calcium Signaling/drug effects ; Dentate Gyrus/drug effects ; Dentate Gyrus/physiology ; Excitatory Postsynaptic Potentials/drug effects ; Hormones/pharmacology ; In Vitro Techniques ; Long-Term Potentiation/drug effects ; Male ; Mice ; Perforant Pathway/drug effects ; Perforant Pathway/physiology ; Somatostatin/pharmacology
Chemical Substances	Hormones ; Somatostatin (51110-01-1) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2002-12
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	80161-6
ISSN	1522-1598 ; 0022-3077
ISSN (online)	1522-1598
ISSN	0022-3077
DOI	10.1152/jn.00398.2002
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Article ; Online: Somatostatin receptor subtype 4 couples to the M-current to regulate seizures.

Qiu, Cuie / Zeyda, Thomas / Johnson, Brian / Hochgeschwender, Ute / de Lecea, Luis / Tallent, Melanie K

The Journal of neuroscience : the official journal of the Society for Neuroscience

2008 Volume 28, Issue 14, Page(s) 3567–3576

Abstract: The K(+) M-current (I(M), Kv7) is an important regulator of cortical excitability, and mutations ...

Abstract	The K(+) M-current (I(M), Kv7) is an important regulator of cortical excitability, and mutations in these channels cause a seizure disorder in humans. The neuropeptide somatostatin (SST), which has antiepileptic properties, augments I(M) in hippocampal CA1 pyramidal neurons. We used SST receptor knock-out mice and subtype-selective ligands to investigate the receptor subtype that couples to I(M) and mediates the antiepileptic effects of SST. Using pentylenetetrazole as a chemoconvulsant, SST(2), SST(3), and SST(4) receptor knock-out mice all had shorter latencies to different seizure stages and increased seizure severity when compared with wild-type mice. However, the most robust differences were observed in the SST(4) knock-outs. When seizures were induced by systemic injection of kainate, only SST(4) knock-outs showed an increase in seizure sensitivity. We next examined the action of SST and subtype-selective SST agonists on electrophysiological parameters in hippocampal slices of wild-type and receptor knock-out mice. SST(2) and SST(4) appear to mediate the majority of SST inhibition of epileptiform activity in CA1. SST lacked presynaptic effects in mouse CA1, in contrast to our previous findings in rat. SST increased I(M) in CA1 pyramidal neurons of wild-type and SST(2) knock-out mice, but not SST(4) knock-out mice. Using M-channel blockers, we found that SST(4) coupling to M-channels is critical to its inhibition of epileptiform activity. This is the first demonstration of an endogenous enhancer of I(M) that is important in controlling seizure activity. SST(4) receptors could therefore be an important novel target for developing new antiepileptic and antiepileptogenic drugs.
MeSH term(s)	Analysis of Variance ; Animals ; Disease Models, Animal ; Dose-Response Relationship, Radiation ; Electric Stimulation/methods ; Hippocampus/cytology ; Hippocampus/drug effects ; Hippocampus/physiopathology ; In Vitro Techniques ; Kainic Acid ; Membrane Potentials/drug effects ; Membrane Potentials/physiology ; Membrane Potentials/radiation effects ; Membrane Proteins/deficiency ; Membrane Proteins/physiology ; Mice ; Mice, Knockout ; Mutation/physiology ; Neurons/drug effects ; Neurons/physiology ; Neurons/radiation effects ; Patch-Clamp Techniques/methods ; Pentylenetetrazole ; Potassium/pharmacology ; Potassium Channel Blockers/pharmacology ; Potassium Channels/drug effects ; Potassium Channels/physiology ; Potassium Channels/radiation effects ; Rats ; Reaction Time/drug effects ; Reaction Time/physiology ; Receptors, Somatostatin/classification ; Receptors, Somatostatin/deficiency ; Receptors, Somatostatin/physiology ; Seizures/chemically induced ; Seizures/genetics ; Seizures/pathology ; Seizures/physiopathology
Chemical Substances	Membrane Proteins ; Potassium Channel Blockers ; Potassium Channels ; Receptors, Somatostatin ; somatostatin receptor subtype-4 ; Potassium (RWP5GA015D) ; Kainic Acid (SIV03811UC) ; Pentylenetetrazole (WM5Z385K7T)
Language	English
Publishing date	2008-03-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.4679-07.2008
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Article: In Vivo Modulation of O-GlcNAc Levels Regulates Hippocampal Synaptic Plasticity through Interplay with Phosphorylation

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

Journal of biological chemistry. 2009 Jan. 2, v. 284, no. 1

2009

Abstract: 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 ... ...

Abstract	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.
Language	English
Dates of publication	2009-0102
Size	p. 174-181.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Bonn / Germany

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