Abstract : NMDA receptor-dependent synaptic modifications such as long-term potentiation (LTP) and long-term d
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Abstract : NMDA receptor-dependent synaptic modifications such as long-term potentiation (LTP) and long-term depression (LTD) are essential for brain development and function. LTD occurs mainly by the removal of AMPA receptors from the postsynaptic membrane but the underlying molecular mechanisms remain unclear. Here we show that activation of caspase-3 via mitochondria is required for LTD and AMPA receptor internalization in hippocampal neurons. LTD and AMPA receptor internalization are blocked by peptide inhibitors of caspase-3 and -9. In hippocampal slices from caspase-3 knockout mice LTD is abolished whereas LTP remains normal. LTD is also prevented by overexpression of the anti-apoptotic proteins XIAP or Bcl-xL and by a mutant Akt1 protein that is resistant to caspase-3 proteolysis. NMDA receptor stimulation that induces LTD transiently activates caspase-3 in dendrites without causing cell death. These data indicate an unexpected causal link between the molecular mechanisms of apoptosis and LTD.Copyright 2010 Elsevier Inc. All rights reserved.PMID 20510932 PubMed - indexed for MEDLINEPMCID PMC2909748Free PMC ArticleImages from this publication.See all images (7) Free text var imageStripObj = } imageStripObj.images = imageStripObj.start = 0 imageStripObj.maxImagesPerView = 7 imageStripObj.count = 7 imageStripObj.containerSelector = ".pmc_images" imageStripObj.CommonCitation = "Cell. Author manuscript available in PMC 2010 November 1.141(5)859-871." imageStripObj.ImageStripLogVal = "image_preview" imageStripObj.ImageStripPreviewLogName = "previewimagepos" Figure 1Caspase inhibitors DEVD- and LEHD-FMK block LTD in CA1 hippocampal neurons. Acute hippocampal slices (from 3–4 week old rats) were incubated with caspase inhibitors for 2 hr before recording (DEVD-FMK 2 µM LEHD-FMK 2 µM FA-FMK 10 µM YVAD-FMK 5 µM). Extracellular field EPSPs were evoked by sti...Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalizationCell. Author manuscript available in PMC 2010 November 1.141(5)859-871.Figure 2Overexpression of Bcl-xL and XIAP constructs blocks LTD in CA1 neurons of organotypic hippocampal slice cultures. CA1 neurons were biolistically transfected with Bcl-xL XIAP-Bir12 XIAP-Bir3 or CrmA (with GFP cotransfected as a visual marker) and recorded in whole-cell patch-clamp mode. (A–C) Pair...Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalizationCell. Author manuscript available in PMC 2010 November 1.141(5)859-871.Figure 3LTD is abolished in hippocampal slices from caspase-3 knockout (-/-) mice. (A) Input-output relationship in caspase-3 -/- and wildtype mice (2–4 weeks age). fEPSP slope was plotted against amplitude of presynaptic volley at four different stimulus intensities (10 µA 20 µA 50 µA and 100 µA). Graph ...Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalizationCell. Author manuscript available in PMC 2010 November 1.141(5)859-871.Figure 4Caspase inhibitors DEVD- and LEHD-FMK block NMDA-induced AMPA receptor internalization. Antibody-feeding internalization assay for endogenous GluR2 (A) and GluR1 (B) in hippocampal neurons stimulated with NMDA (50 µM for 10 min). Neurons were pretreated with various caspase inhibitors (5 µM) as indi...Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalizationCell. Author manuscript available in PMC 2010 November 1.141(5)859-871.Figure 5Anti-apoptotic proteins inhibit AMPA receptor internalization. Cultured hippocampal neurons (DIV14) were transfected with Bcl-xL XIAP-Bir12 XIAP-Bir3 or CrmA or control ß-gal. At 2–4 days after transfection neurons were treated with NMDA as indicated and GluR2 (A) and GluR1 internalization (B)...Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalizationCell. Author manuscript available in PMC 2010 November 1.141(5)859-871.Figure 6Transient activation of caspase-3 in neurons by NMDA. (A D E) Immunoblots showing cleaved (active) caspase-3 and caspase-9 and cytosolic cytochrome c in cortical neuronal cultures (DIV18) at various times after treatment with NMDA (50 µM for 10 min) or staurosporine (STS 1 µM throughout the expe...Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalizationCell. Author manuscript available in PMC 2010 November 1.141(5)859-871.Figure 7Overexpression of caspase-3-resistant triple mutant of Akt1 (D108A/D119A/D462N) blocks LTD in CA1 neurons of organotypic hippocampal slice cultures. (A) Cleavage of wildtype or mutant Akt1 proteins by caspase-3 in vitro. In vitro translated WT Akt1 D108A/D119A/D462N triple mutant or Quadruple mutant were i...Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalizationCell. Author manuscript available in PMC 2010 November 1.141(5)859-871. imageStripObj.images0= ImageUrl"/pmc/articles/instance/2909748/bin/nihms214681f1.jpg" ImageSource"/pmc/articles/PMC2909748/figure/F1/" ThumbUrl"/pmc/articles/instance/2909748/bin/nihms214681f1.gif" Label"Figure201" SourceId"/pmc/articles/PMC2909748/" CaptionTitle"" Caption"Caspase inhibitors DEVD- and LEHD-FMK block LTD in CA1 hippocampal neurons. Acute hippocampal slices (from 3–4 week old rats) were incubated with caspase inhibitors for 2 hr before recording (DEVD-FMK 2 µM LEHD-FMK 2 µM FA-FMK 10 µM YVAD-FMK 5 µM). Extracellular field EPSPs were evoked by sti..." ArticleTitle"Caspase-320activation20via20mitochondria20is20required20for20long-term20depression20and20AMPA20receptor20internalization" ImagePosition"1" Citation"Cell. Author manuscript available in PMC 2010 November 1.141(5)859-871." } imageStripObj.images1= ImageUrl"/pmc/articles/instance/2909748/bin/nihms214681f2.jpg" ImageSource"/pmc/articles/PMC2909748/figure/F2/" ThumbUrl"/pmc/articles/instance/2909748/bin/nihms214681f2.gif" Label"Figure202" SourceId"/pmc/articles/PMC2909748/" CaptionTitle"" Caption"Overexpression of Bcl-xL and XIAP constructs blocks LTD in CA1 neurons of organotypic hippocampal slice cultures. CA1 neurons were biolistically transfected with Bcl-xL XIAP-Bir12 XIAP-Bir3 or CrmA (with GFP cotransfected as a visual marker) and recorded in whole-cell patch-clamp mode. (A–C) Pair..." ArticleTitle"Caspase-320activation20via20mitochondria20is20required20for20long-term20depression20and20AMPA20receptor20internalization" ImagePosition"2" Citation"Cell. Author manuscript available in PMC 2010 November 1.141(5)859-871." } imageStripObj.images2= ImageUrl"/pmc/articles/instance/2909748/bin/nihms214681f3.jpg" ImageSource"/pmc/articles/PMC2909748/figure/F3/" ThumbUrl"/pmc/articles/instance/2909748/bin/nihms214681f3.gif" Label"Figure203" SourceId"/pmc/articles/PMC2909748/" CaptionTitle"" Caption"LTD is abolished in hippocampal slices from caspase-3 knockout (-/-) mice. (A) Input-output relationship in caspase-3 -/- and wildtype mice (2–4 weeks age). fEPSP slope was plotted against amplitude of presynaptic volley at four different stimulus intensities (10 µA 20 µA 50 µA and 100 µA). Graph ..." ArticleTitle"Caspase-320activation20via20mitochondria20is20required20for20long-term20depression20and20AMPA20receptor20internalization" ImagePosition"3" Citation"Cell. Author manuscript available in PMC 2010 November 1.141(5)859-871." } imageStripObj.images3= ImageUrl"/pmc/articles/instance/2909748/bin/nihms214681f4.jpg" ImageSource"/pmc/articles/PMC2909748/figure/F4/" ThumbUrl"/pmc/articles/instance/2909748/bin/nihms214681f4.gif" Label"Figure204" SourceId"/pmc/articles/PMC2909748/" CaptionTitle"" Caption"Caspase inhibitors DEVD- and LEHD-FMK block NMDA-induced AMPA receptor internalization. Antibody-feeding internalization assay for endogenous GluR2 (A) and GluR1 (B) in hippocampal neurons stimulated with NMDA (50 µM for 10 min). Neurons were pretreated with various caspase inhibitors (5 µM) as indi..." ArticleTitle"Caspase-320activation20via20mitochondria20is20required20for20long-term20depression20and20AMPA20receptor20internalization" ImagePosition"4" Citation"Cell. Author manuscript available in PMC 2010 November 1.141(5)859-871." } imageStripObj.images4= ImageUrl"/pmc/articles/instance/2909748/bin/nihms214681f5.jpg" ImageSource"/pmc/articles/PMC2909748/figure/F5/" ThumbUrl"/pmc/articles/instance/2909748/bin/nihms214681f5.gif" Label"Figure205" SourceId"/pmc/articles/PMC2909748/" CaptionTitle"" Caption"Anti-apoptotic proteins inhibit AMPA receptor internalization. Cultured hippocampal neurons (DIV14) were transfected with Bcl-xL XIAP-Bir12 XIAP-Bir3 or CrmA or control ß-gal. At 2–4 days after transfection neurons were treated with NMDA as indicated and GluR2 (A) and GluR1 internalization (B)..." ArticleTitle"Caspase-320activation20via20mitochondria20is20required20for20long-term20depression20and20AMPA20receptor20internalization" ImagePosition"5" Citation"Cell. Author manuscript available in PMC 2010 November 1.141(5)859-871." } imageStripObj.images5= ImageUrl"/pmc/articles/instance/2909748/bin/nihms214681f6.jpg" ImageSource"/pmc/articles/PMC2909748/figure/F6/" ThumbUrl"/pmc/articles/instance/2909748/bin/nihms214681f6.gif" Label"Figure206" SourceId"/pmc/articles/PMC2909748/" CaptionTitle"" Caption"Transient activation of caspase-3 in neurons by NMDA. (A D E) Immunoblots showing cleaved (active) caspase-3 and caspase-9 and cytosolic cytochrome c in cortical neuronal cultures (DIV18) at various times after treatment with NMDA (50 µM for 10 min) or staurosporine (STS 1 µM throughout the expe..." ArticleTitle"Caspase-320activation20via20mitochondria20is20required20for20long-term20depression20and20AMPA20receptor20internalization" ImagePosition"6" Citation"Cell. Author manuscript available in PMC 2010 November 1.141(5)859-871." } imageStripObj.images6= ImageUrl"/pmc/articles/instance/2909748/bin/nihms214681f7.jpg" ImageSource"/pmc/articles/PMC2909748/figure/F7/" ThumbUrl"/pmc/articles/instance/2909748/bin/nihms214681f7.gif" Label"Figure207" SourceId"/pmc/articles/PMC2909748/" CaptionTitle"" Caption"Overexpression of caspase-3-resistant triple mutant of Akt1 (D108A/D119A/D462N) blocks LTD in CA1 neurons of organotypic hippocampal slice cultures. (A) Cleavage of wildtype or mutant Akt1 proteins by caspase-3 in vitro. In vitro translated WT Akt1 D108A/D119A/D462N triple mutant or Quadruple mutant were i..." ArticleTitle"Caspase-320activation20via20mitochondria20is20required20for20long-term20depression20and20AMPA20receptor20internalization" ImagePosition"7" Citation"Cell. Author manuscript available in PMC 2010 November 1.141(5)859-871." } imageStripObj.containerSelector=".pmc_images" imageStripObj.minWidth=410 Publication Types MeSH Terms Substances Grant SupportPublication Types Research Support N.I.H. ExtramuralResearch Support N.I.H. IntramuralResearch Support Non-U.S. GovtMeSH TermsAnimalsApoptosis*Caspase 3/metabolism*Cells CulturedCytochromes c/metabolismHippocampus/cytologyHippocampus/metabolism*Long-Term PotentiationLong-Term Synaptic Depression*MiceMice KnockoutProto-Oncogene Proteins c-akt/geneticsProto-Oncogene Proteins c-akt/metabolismRatsRats WistarReceptors AMPA/metabolism*Receptors N-Methyl-D-Aspartate/metabolismX-Linked Inhibitor of Apoptosis Protein/metabolismbcl-X Protein/metabolismSubstancesReceptors AMPAReceptors N-Methyl-D-AspartateX-Linked Inhibitor of Apoptosis Proteinbcl-X ProteinCytochromes cProto-Oncogene Proteins c-aktCaspase 3Grant SupportF32-NS046126/NS/NINDS NIH HHS/United StatesZ01 MH002881-01/MH/NIMH NIH HHS/United StatesZ01 MH002881-02/MH/NIMH NIH HHS/United StatesZIA MH002881-03/MH/NIMH NIH HHS/United StatesBiotechnology and Biological Sciences Research Council/United KingdomLinkOut - more resourcesFull Text SourcesElsevier ScienceEBSCOOhioLINK Electronic Journal CenterPubMed Central - Author ManuscriptPubMed Central Canada - Author ManuscriptSwets Information ServicesUK PubMed Central - Author ManuscriptOther Literature SourcesCOS Scholar UniverseEvaluations and comments from leading biologists - Faculty of 1000 Biology Supplemental Content Related citations Critical differences in magnitude and duration of N-methyl D-aspartate(NMDA) receptor activation between long-term potentiation (LTP) and long-term depression (LTD) induction. Acta Med Okayama. 2008 Critical differences in magnitude and duration of N-methyl D-aspartate(NMDA) receptor activation between long-term potentiation (LTP) and long-term depression (LTD) induction.Taniike N Lu YF Tomizawa K Matsui H. Acta Med Okayama. 2008 Feb 62(1)21-8. PDZ protein mediated activity-dependent LTP/LTD developmental switch at rat retinocollicular synapses. Am J Physiol Cell Physiol. 2010 PDZ protein mediated activity-dependent LTP/LTD developmental switch at rat retinocollicular synapses.Xue L Zhang F Chen X Lin J Shi J. Am J Physiol Cell Physiol. 2010 Jun 298(6)C1572-82. Epub 2010 Mar 24. Evidence that caspase-1 is a negative regulator of AMPA receptor-mediated long-term potentiation at hippocampal synapses. J Neurochem. 2006 Evidence that caspase-1 is a negative regulator of AMPA receptor-mediated long-term potentiation at hippocampal synapses.Lu C Wang Y Furukawa K Fu W Ouyang X Mattson MP. J Neurochem. 2006 May 97(4)1104-10. Epub 2006 Mar 29. Review Regulation of neuronal PKA signaling through AKAP targeting dynamics. Eur J Cell Biol. 2006 Review Regulation of neuronal PKA signaling through AKAP targeting dynamics.DellAcqua ML Smith KE Gorski JA Horne EA Gibson ES Gomez LL. Eur J Cell Biol. 2006 Jul 85(7)627-33. Epub 2006 Feb 28. Review Plasticity hippocampal place cells and cognitive maps. Arch Neurol. 2001 Review Plasticity hippocampal place cells and cognitive maps.Shapiro M. Arch Neurol. 2001 Jun 58(6)874-81. See reviews... See all... Cited by 1 PubMed Central article Mitochondria and neuroplasticity. ASN Neuro. 2010 Mitochondria and neuroplasticity.Cheng A Hou Y Mattson MP. ASN Neuro. 2010 Oct 4 2(5). Epub 2010 Oct 4. All links from this record Related Citations Calculated set of PubMed citations closely related to the selected article(s) retrieved using a word weight algorithm. Related articles are displayed in ranked order from most to least relevant with the “linked from” citation displayed first. 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