Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Neurosci
2011 Jan 19;313:899-906. doi: 10.1523/JNEUROSCI.4625-10.2011.
Show Gene links
Show Anatomy links
A novel role for {gamma}-secretase: selective regulation of spontaneous neurotransmitter release from hippocampal neurons.
Pratt KG
,
Zhu P
,
Watari H
,
Cook DG
,
Sullivan JM
.
???displayArticle.abstract???
With a multitude of substrates, γ-secretase is poised to control neuronal function through a variety of signaling pathways. Presenilin 1 (PS1) is an integral component of γ-secretase and is also a protein closely linked to the etiology of Alzheimer's disease (AD). To better understand the roles of γ-secretase and PS1 in normal and pathological synaptic transmission, we examined evoked and spontaneous neurotransmitter release in cultured hippocampal neurons derived from PS1 knock-out (KO) mice. We found no changes in the size of evoked synaptic currents, short-term plasticity, or apparent calcium dependence of evoked release. The rate of spontaneous release from PS1 KO neurons was, however, approximately double that observed in wild-type (WT) neurons. This increase in spontaneous neurotransmission depended on calcium influx but did not require activation of voltage-gated calcium channels or presynaptic NMDA receptors or release of calcium from internal stores. The rate of spontaneous release from PS1 KO neurons was significantly reduced by lentivirus-mediated expression of WT PS1 or familial AD-linked M146V PS1, but not the D257A PS1 mutant that does not support γ-secretase activity. Treatment of WT neuronal cultures with γ-secretase inhibitor mimicked the loss of PS1, leading to a selective increase in spontaneous release without any change in the size of evoked synaptic currents. Together, these results identify a novel role for γ-secretase in the control of spontaneous neurotransmission through modulation of low-level tonic calcium influx into presynaptic axon terminals.
Barry,
Lentivirus vectors encoding both central polypurine tract and posttranscriptional regulatory element provide enhanced transduction and transgene expression.
2001, Pubmed
Barry,
Lentivirus vectors encoding both central polypurine tract and posttranscriptional regulatory element provide enhanced transduction and transgene expression.
2001,
Pubmed
Bezprozvanny,
Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease.
2008,
Pubmed
Bollmann,
Calcium sensitivity of glutamate release in a calyx-type terminal.
2000,
Pubmed
Carter,
Assessing the role of calcium-induced calcium release in short-term presynaptic plasticity at excitatory central synapses.
2002,
Pubmed
Chakroborty,
Deviant ryanodine receptor-mediated calcium release resets synaptic homeostasis in presymptomatic 3xTg-AD mice.
2009,
Pubmed
Cheung,
Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating.
2008,
Pubmed
Cook,
Presenilin 1 deficiency alters the activity of voltage-gated Ca2+ channels in cultured cortical neurons.
2005,
Pubmed
Corlew,
Presynaptic NMDA receptors: newly appreciated roles in cortical synaptic function and plasticity.
2008,
Pubmed
De Strooper,
Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex.
2003,
Pubmed
De Strooper,
Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
1998,
Pubmed
Dewachter,
Modulation of synaptic plasticity and Tau phosphorylation by wild-type and mutant presenilin1.
2008,
Pubmed
Emptage,
Calcium stores in hippocampal synaptic boutons mediate short-term plasticity, store-operated Ca2+ entry, and spontaneous transmitter release.
2001,
Pubmed
Espinosa,
NMDA receptor activation by spontaneous glutamatergic neurotransmission.
2009,
Pubmed
Feng,
Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces.
2001,
Pubmed
Fox,
Kinetic and pharmacological properties distinguishing three types of calcium currents in chick sensory neurones.
1987,
Pubmed
Kamenetz,
APP processing and synaptic function.
2003,
Pubmed
LaFerla,
Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease.
2002,
Pubmed
Lou,
Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion.
2005,
Pubmed
McKinney,
Miniature synaptic events maintain dendritic spines via AMPA receptor activation.
1999,
Pubmed
Morton,
Impairment in hippocampal long-term potentiation in mice under-expressing the Alzheimer's disease related gene presenilin-1.
2002,
Pubmed
Panza,
REVIEW: γ-Secretase inhibitors for the treatment of Alzheimer's disease: The current state.
2010,
Pubmed
Parent,
Presenilin attenuates receptor-mediated signaling and synaptic function.
2005,
Pubmed
Ris,
Capacitative calcium entry induces hippocampal long term potentiation in the absence of presenilin-1.
2003,
Pubmed
Rybalchenko,
The cytosolic N-terminus of presenilin-1 potentiates mouse ryanodine receptor single channel activity.
2008,
Pubmed
Schneggenburger,
Intracellular calcium dependence of transmitter release rates at a fast central synapse.
2000,
Pubmed
Sharma,
Modulation of presynaptic store calcium induces release of glutamate and postsynaptic firing.
2003,
Pubmed
Shen,
Skeletal and CNS defects in Presenilin-1-deficient mice.
1997,
Pubmed
Stevens,
The synaptotagmin C2A domain is part of the calcium sensor controlling fast synaptic transmission.
2003,
Pubmed
Stutzmann,
Calcium dysregulation, IP3 signaling, and Alzheimer's disease.
2005,
Pubmed
Sutton,
Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis.
2006,
Pubmed
Tanzi,
New frontiers in Alzheimer's disease genetics.
2001,
Pubmed
Thinakaran,
Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo.
1996,
Pubmed
Tu,
Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations.
2006,
Pubmed
Wolfe,
Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.
1999,
Pubmed
Yang,
Presenilin-1 deficiency impairs glutamate-evoked intracellular calcium responses in neurons.
2004,
Pubmed
Yoo,
Presenilin-mediated modulation of capacitative calcium entry.
2000,
Pubmed
Yu,
APP processing and synaptic plasticity in presenilin-1 conditional knockout mice.
2001,
Pubmed
Zhang,
Presenilins are essential for regulating neurotransmitter release.
2009,
Pubmed
Zucker,
Short-term synaptic plasticity.
2002,
Pubmed
