Synaptotagmin-2 is essential for survival and contributes to Ca 2+ triggering of neurotransmitter release in central and neuromuscular synapses

Zhiping P. Pang, Ernestina Melicoff, Daniel Padgett, Yun Liu, Andrew F. Teich, Burton F. Dickey, Weichun Lin, Roberto Adachi, Thomas C. Südhof

Research output: Contribution to journalArticle

121 Citations (Scopus)

Abstract

Biochemical and genetic data suggest that synaptotagmin-2 functions as a Ca2+ sensor for fast neurotransmitter release in caudal brain regions, but animals and/or synapses lacking synaptotagmin-2 have not been examined. We have now generated mice in which the 5′ end of the synaptotagmin-2 gene was replaced by lacZ. Using β-galactosidase as a marker, we show that, consistent with previous studies, synaptotagmin-2 is widely expressed in spinal cord, brainstem, and cerebellum, but is additionally present in selected forebrain neurons, including most striatal neurons and some hypothalamic, cortical, and hippocampal neurons. Synaptotagmin-2-deficient mice were indistinguishable from wild-type littermates at birth, but subsequently developed severe motor dysfunction, and perished at ∼3 weeks of age. Electrophysiological studies in cultured striatal neurons revealed that the synaptotagmin-2 deletion slowed the kinetics of evoked neurotransmitter release without altering the total amount of release. In contrast, synaptotagmin-2- deficient neuromuscular junctions (NMJs) suffered from a large reduction in evoked release and changes in short-term synaptic plasticity. Furthermore, in mutant NMJs, the frequency of spontaneous miniature release events was increased both at rest and during stimulus trains. Viewed together, our results demonstrate that the synaptotagmin-2 deficiency causes a lethal impairment in synaptic transmission in selected synapses. This impairment, however, is less severe than that produced in forebrain neurons by deletion of synaptotagmin-1, presumably because at least in NMJs, synaptotagmin-1 is coexpressed with synaptotagmin-2, and both together mediate fast Ca2+-triggered release. Thus, synaptotagmin-2 is an essential synaptotagmin isoform that functions in concert with other synaptotagmins in the Ca2+ triggering of neurotransmitter release.

Original languageEnglish (US)
Pages (from-to)13493-13504
Number of pages12
JournalJournal of Neuroscience
Volume26
Issue number52
DOIs
StatePublished - Dec 27 2006

Fingerprint

Synaptotagmin II
Synapses
Neurotransmitter Agents
Neuromuscular Junction
Neurons
Synaptotagmin I
Synaptotagmins
Corpus Striatum
Prosencephalon
Galactosidases
Neuronal Plasticity
Synaptic Transmission
Cerebellum
Brain Stem

Keywords

  • Asynchronous release
  • Endplate
  • Neuromuscular junction
  • Striatum
  • Synapse
  • Synaptotagmin

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Synaptotagmin-2 is essential for survival and contributes to Ca 2+ triggering of neurotransmitter release in central and neuromuscular synapses. / Pang, Zhiping P.; Melicoff, Ernestina; Padgett, Daniel; Liu, Yun; Teich, Andrew F.; Dickey, Burton F.; Lin, Weichun; Adachi, Roberto; Südhof, Thomas C.

In: Journal of Neuroscience, Vol. 26, No. 52, 27.12.2006, p. 13493-13504.

Research output: Contribution to journalArticle

Pang, Zhiping P. ; Melicoff, Ernestina ; Padgett, Daniel ; Liu, Yun ; Teich, Andrew F. ; Dickey, Burton F. ; Lin, Weichun ; Adachi, Roberto ; Südhof, Thomas C. / Synaptotagmin-2 is essential for survival and contributes to Ca 2+ triggering of neurotransmitter release in central and neuromuscular synapses. In: Journal of Neuroscience. 2006 ; Vol. 26, No. 52. pp. 13493-13504.
@article{c3116aaf395c4a19982262ae7e0b4aad,
title = "Synaptotagmin-2 is essential for survival and contributes to Ca 2+ triggering of neurotransmitter release in central and neuromuscular synapses",
abstract = "Biochemical and genetic data suggest that synaptotagmin-2 functions as a Ca2+ sensor for fast neurotransmitter release in caudal brain regions, but animals and/or synapses lacking synaptotagmin-2 have not been examined. We have now generated mice in which the 5′ end of the synaptotagmin-2 gene was replaced by lacZ. Using β-galactosidase as a marker, we show that, consistent with previous studies, synaptotagmin-2 is widely expressed in spinal cord, brainstem, and cerebellum, but is additionally present in selected forebrain neurons, including most striatal neurons and some hypothalamic, cortical, and hippocampal neurons. Synaptotagmin-2-deficient mice were indistinguishable from wild-type littermates at birth, but subsequently developed severe motor dysfunction, and perished at ∼3 weeks of age. Electrophysiological studies in cultured striatal neurons revealed that the synaptotagmin-2 deletion slowed the kinetics of evoked neurotransmitter release without altering the total amount of release. In contrast, synaptotagmin-2- deficient neuromuscular junctions (NMJs) suffered from a large reduction in evoked release and changes in short-term synaptic plasticity. Furthermore, in mutant NMJs, the frequency of spontaneous miniature release events was increased both at rest and during stimulus trains. Viewed together, our results demonstrate that the synaptotagmin-2 deficiency causes a lethal impairment in synaptic transmission in selected synapses. This impairment, however, is less severe than that produced in forebrain neurons by deletion of synaptotagmin-1, presumably because at least in NMJs, synaptotagmin-1 is coexpressed with synaptotagmin-2, and both together mediate fast Ca2+-triggered release. Thus, synaptotagmin-2 is an essential synaptotagmin isoform that functions in concert with other synaptotagmins in the Ca2+ triggering of neurotransmitter release.",
keywords = "Asynchronous release, Endplate, Neuromuscular junction, Striatum, Synapse, Synaptotagmin",
author = "Pang, {Zhiping P.} and Ernestina Melicoff and Daniel Padgett and Yun Liu and Teich, {Andrew F.} and Dickey, {Burton F.} and Weichun Lin and Roberto Adachi and S{\"u}dhof, {Thomas C.}",
year = "2006",
month = "12",
day = "27",
doi = "10.1523/JNEUROSCI.3519-06.2006",
language = "English (US)",
volume = "26",
pages = "13493--13504",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "52",

}

TY - JOUR

T1 - Synaptotagmin-2 is essential for survival and contributes to Ca 2+ triggering of neurotransmitter release in central and neuromuscular synapses

AU - Pang, Zhiping P.

AU - Melicoff, Ernestina

AU - Padgett, Daniel

AU - Liu, Yun

AU - Teich, Andrew F.

AU - Dickey, Burton F.

AU - Lin, Weichun

AU - Adachi, Roberto

AU - Südhof, Thomas C.

PY - 2006/12/27

Y1 - 2006/12/27

N2 - Biochemical and genetic data suggest that synaptotagmin-2 functions as a Ca2+ sensor for fast neurotransmitter release in caudal brain regions, but animals and/or synapses lacking synaptotagmin-2 have not been examined. We have now generated mice in which the 5′ end of the synaptotagmin-2 gene was replaced by lacZ. Using β-galactosidase as a marker, we show that, consistent with previous studies, synaptotagmin-2 is widely expressed in spinal cord, brainstem, and cerebellum, but is additionally present in selected forebrain neurons, including most striatal neurons and some hypothalamic, cortical, and hippocampal neurons. Synaptotagmin-2-deficient mice were indistinguishable from wild-type littermates at birth, but subsequently developed severe motor dysfunction, and perished at ∼3 weeks of age. Electrophysiological studies in cultured striatal neurons revealed that the synaptotagmin-2 deletion slowed the kinetics of evoked neurotransmitter release without altering the total amount of release. In contrast, synaptotagmin-2- deficient neuromuscular junctions (NMJs) suffered from a large reduction in evoked release and changes in short-term synaptic plasticity. Furthermore, in mutant NMJs, the frequency of spontaneous miniature release events was increased both at rest and during stimulus trains. Viewed together, our results demonstrate that the synaptotagmin-2 deficiency causes a lethal impairment in synaptic transmission in selected synapses. This impairment, however, is less severe than that produced in forebrain neurons by deletion of synaptotagmin-1, presumably because at least in NMJs, synaptotagmin-1 is coexpressed with synaptotagmin-2, and both together mediate fast Ca2+-triggered release. Thus, synaptotagmin-2 is an essential synaptotagmin isoform that functions in concert with other synaptotagmins in the Ca2+ triggering of neurotransmitter release.

AB - Biochemical and genetic data suggest that synaptotagmin-2 functions as a Ca2+ sensor for fast neurotransmitter release in caudal brain regions, but animals and/or synapses lacking synaptotagmin-2 have not been examined. We have now generated mice in which the 5′ end of the synaptotagmin-2 gene was replaced by lacZ. Using β-galactosidase as a marker, we show that, consistent with previous studies, synaptotagmin-2 is widely expressed in spinal cord, brainstem, and cerebellum, but is additionally present in selected forebrain neurons, including most striatal neurons and some hypothalamic, cortical, and hippocampal neurons. Synaptotagmin-2-deficient mice were indistinguishable from wild-type littermates at birth, but subsequently developed severe motor dysfunction, and perished at ∼3 weeks of age. Electrophysiological studies in cultured striatal neurons revealed that the synaptotagmin-2 deletion slowed the kinetics of evoked neurotransmitter release without altering the total amount of release. In contrast, synaptotagmin-2- deficient neuromuscular junctions (NMJs) suffered from a large reduction in evoked release and changes in short-term synaptic plasticity. Furthermore, in mutant NMJs, the frequency of spontaneous miniature release events was increased both at rest and during stimulus trains. Viewed together, our results demonstrate that the synaptotagmin-2 deficiency causes a lethal impairment in synaptic transmission in selected synapses. This impairment, however, is less severe than that produced in forebrain neurons by deletion of synaptotagmin-1, presumably because at least in NMJs, synaptotagmin-1 is coexpressed with synaptotagmin-2, and both together mediate fast Ca2+-triggered release. Thus, synaptotagmin-2 is an essential synaptotagmin isoform that functions in concert with other synaptotagmins in the Ca2+ triggering of neurotransmitter release.

KW - Asynchronous release

KW - Endplate

KW - Neuromuscular junction

KW - Striatum

KW - Synapse

KW - Synaptotagmin

UR - http://www.scopus.com/inward/record.url?scp=33845900184&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33845900184&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.3519-06.2006

DO - 10.1523/JNEUROSCI.3519-06.2006

M3 - Article

C2 - 17192432

AN - SCOPUS:33845900184

VL - 26

SP - 13493

EP - 13504

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 52

ER -