The two faces of synaptic failure in App NL-G-F knock-in mice

Abstract Background Intensive basic and preclinical research into Alzheimer’s disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and t...
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Autor*in:	Amira Latif-Hernandez [verfasserIn] Victor Sabanov [verfasserIn] Tariq Ahmed [verfasserIn] Katleen Craessaerts [verfasserIn] Takashi Saito [verfasserIn] Takaomi Saido [verfasserIn] Detlef Balschun [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Schlagwörter:	App knock-in mice Long-term potentiation Long-term depression Miniature synaptic currents Presynaptic glutamatergic and GABAergic upregulation Electrophysiological phenotyping

Übergeordnetes Werk:	In: Alzheimer’s Research & Therapy - BMC, 2015, 12(2020), 1, Seite 15
Übergeordnetes Werk:	volume:12 ; year:2020 ; number:1 ; pages:15

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1186/s13195-020-00667-6

Katalog-ID:	DOAJ053211693

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520			\|a Abstract Background Intensive basic and preclinical research into Alzheimer’s disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in “preclinical AD.” Methods Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in App NL-G-F mice compared to App NL animals which served as controls. Results We found a beginning synaptic impairment (LTP deficit) at 3–4 months in the prefrontal cortex of App NL-G-F mice that is further aggravated and extended to the hippocampus at 6–8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function. Conclusions Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function.
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653		0	\|a Neurosciences. Biological psychiatry. Neuropsychiatry
653		0	\|a Neurology. Diseases of the nervous system
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allfields	10.1186/s13195-020-00667-6 doi (DE-627)DOAJ053211693 (DE-599)DOAJ1e4786f2544f436092354c5f169b3626 DE-627 ger DE-627 rakwb eng RC321-571 RC346-429 Amira Latif-Hernandez verfasserin aut The two faces of synaptic failure in App NL-G-F knock-in mice 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Intensive basic and preclinical research into Alzheimer’s disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in “preclinical AD.” Methods Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in App NL-G-F mice compared to App NL animals which served as controls. Results We found a beginning synaptic impairment (LTP deficit) at 3–4 months in the prefrontal cortex of App NL-G-F mice that is further aggravated and extended to the hippocampus at 6–8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function. Conclusions Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function. App knock-in mice Long-term potentiation Long-term depression Miniature synaptic currents Presynaptic glutamatergic and GABAergic upregulation Electrophysiological phenotyping Neurosciences. Biological psychiatry. Neuropsychiatry Neurology. Diseases of the nervous system Victor Sabanov verfasserin aut Tariq Ahmed verfasserin aut Katleen Craessaerts verfasserin aut Takashi Saito verfasserin aut Takaomi Saido verfasserin aut Detlef Balschun verfasserin aut In Alzheimer’s Research & Therapy BMC, 2015 12(2020), 1, Seite 15 (DE-627)605683557 (DE-600)2506521-X 17589193 nnns volume:12 year:2020 number:1 pages:15 https://doi.org/10.1186/s13195-020-00667-6 kostenfrei https://doaj.org/article/1e4786f2544f436092354c5f169b3626 kostenfrei http://link.springer.com/article/10.1186/s13195-020-00667-6 kostenfrei https://doaj.org/toc/1758-9193 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 1 15
spelling	10.1186/s13195-020-00667-6 doi (DE-627)DOAJ053211693 (DE-599)DOAJ1e4786f2544f436092354c5f169b3626 DE-627 ger DE-627 rakwb eng RC321-571 RC346-429 Amira Latif-Hernandez verfasserin aut The two faces of synaptic failure in App NL-G-F knock-in mice 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Intensive basic and preclinical research into Alzheimer’s disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in “preclinical AD.” Methods Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in App NL-G-F mice compared to App NL animals which served as controls. Results We found a beginning synaptic impairment (LTP deficit) at 3–4 months in the prefrontal cortex of App NL-G-F mice that is further aggravated and extended to the hippocampus at 6–8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function. Conclusions Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function. App knock-in mice Long-term potentiation Long-term depression Miniature synaptic currents Presynaptic glutamatergic and GABAergic upregulation Electrophysiological phenotyping Neurosciences. Biological psychiatry. Neuropsychiatry Neurology. Diseases of the nervous system Victor Sabanov verfasserin aut Tariq Ahmed verfasserin aut Katleen Craessaerts verfasserin aut Takashi Saito verfasserin aut Takaomi Saido verfasserin aut Detlef Balschun verfasserin aut In Alzheimer’s Research & Therapy BMC, 2015 12(2020), 1, Seite 15 (DE-627)605683557 (DE-600)2506521-X 17589193 nnns volume:12 year:2020 number:1 pages:15 https://doi.org/10.1186/s13195-020-00667-6 kostenfrei https://doaj.org/article/1e4786f2544f436092354c5f169b3626 kostenfrei http://link.springer.com/article/10.1186/s13195-020-00667-6 kostenfrei https://doaj.org/toc/1758-9193 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 1 15
allfields_unstemmed	10.1186/s13195-020-00667-6 doi (DE-627)DOAJ053211693 (DE-599)DOAJ1e4786f2544f436092354c5f169b3626 DE-627 ger DE-627 rakwb eng RC321-571 RC346-429 Amira Latif-Hernandez verfasserin aut The two faces of synaptic failure in App NL-G-F knock-in mice 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Intensive basic and preclinical research into Alzheimer’s disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in “preclinical AD.” Methods Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in App NL-G-F mice compared to App NL animals which served as controls. Results We found a beginning synaptic impairment (LTP deficit) at 3–4 months in the prefrontal cortex of App NL-G-F mice that is further aggravated and extended to the hippocampus at 6–8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function. Conclusions Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function. App knock-in mice Long-term potentiation Long-term depression Miniature synaptic currents Presynaptic glutamatergic and GABAergic upregulation Electrophysiological phenotyping Neurosciences. Biological psychiatry. Neuropsychiatry Neurology. Diseases of the nervous system Victor Sabanov verfasserin aut Tariq Ahmed verfasserin aut Katleen Craessaerts verfasserin aut Takashi Saito verfasserin aut Takaomi Saido verfasserin aut Detlef Balschun verfasserin aut In Alzheimer’s Research & Therapy BMC, 2015 12(2020), 1, Seite 15 (DE-627)605683557 (DE-600)2506521-X 17589193 nnns volume:12 year:2020 number:1 pages:15 https://doi.org/10.1186/s13195-020-00667-6 kostenfrei https://doaj.org/article/1e4786f2544f436092354c5f169b3626 kostenfrei http://link.springer.com/article/10.1186/s13195-020-00667-6 kostenfrei https://doaj.org/toc/1758-9193 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 1 15
allfieldsGer	10.1186/s13195-020-00667-6 doi (DE-627)DOAJ053211693 (DE-599)DOAJ1e4786f2544f436092354c5f169b3626 DE-627 ger DE-627 rakwb eng RC321-571 RC346-429 Amira Latif-Hernandez verfasserin aut The two faces of synaptic failure in App NL-G-F knock-in mice 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Intensive basic and preclinical research into Alzheimer’s disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in “preclinical AD.” Methods Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in App NL-G-F mice compared to App NL animals which served as controls. Results We found a beginning synaptic impairment (LTP deficit) at 3–4 months in the prefrontal cortex of App NL-G-F mice that is further aggravated and extended to the hippocampus at 6–8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function. Conclusions Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function. App knock-in mice Long-term potentiation Long-term depression Miniature synaptic currents Presynaptic glutamatergic and GABAergic upregulation Electrophysiological phenotyping Neurosciences. Biological psychiatry. Neuropsychiatry Neurology. Diseases of the nervous system Victor Sabanov verfasserin aut Tariq Ahmed verfasserin aut Katleen Craessaerts verfasserin aut Takashi Saito verfasserin aut Takaomi Saido verfasserin aut Detlef Balschun verfasserin aut In Alzheimer’s Research & Therapy BMC, 2015 12(2020), 1, Seite 15 (DE-627)605683557 (DE-600)2506521-X 17589193 nnns volume:12 year:2020 number:1 pages:15 https://doi.org/10.1186/s13195-020-00667-6 kostenfrei https://doaj.org/article/1e4786f2544f436092354c5f169b3626 kostenfrei http://link.springer.com/article/10.1186/s13195-020-00667-6 kostenfrei https://doaj.org/toc/1758-9193 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 1 15
allfieldsSound	10.1186/s13195-020-00667-6 doi (DE-627)DOAJ053211693 (DE-599)DOAJ1e4786f2544f436092354c5f169b3626 DE-627 ger DE-627 rakwb eng RC321-571 RC346-429 Amira Latif-Hernandez verfasserin aut The two faces of synaptic failure in App NL-G-F knock-in mice 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Intensive basic and preclinical research into Alzheimer’s disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in “preclinical AD.” Methods Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in App NL-G-F mice compared to App NL animals which served as controls. Results We found a beginning synaptic impairment (LTP deficit) at 3–4 months in the prefrontal cortex of App NL-G-F mice that is further aggravated and extended to the hippocampus at 6–8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function. Conclusions Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function. App knock-in mice Long-term potentiation Long-term depression Miniature synaptic currents Presynaptic glutamatergic and GABAergic upregulation Electrophysiological phenotyping Neurosciences. Biological psychiatry. Neuropsychiatry Neurology. Diseases of the nervous system Victor Sabanov verfasserin aut Tariq Ahmed verfasserin aut Katleen Craessaerts verfasserin aut Takashi Saito verfasserin aut Takaomi Saido verfasserin aut Detlef Balschun verfasserin aut In Alzheimer’s Research & Therapy BMC, 2015 12(2020), 1, Seite 15 (DE-627)605683557 (DE-600)2506521-X 17589193 nnns volume:12 year:2020 number:1 pages:15 https://doi.org/10.1186/s13195-020-00667-6 kostenfrei https://doaj.org/article/1e4786f2544f436092354c5f169b3626 kostenfrei http://link.springer.com/article/10.1186/s13195-020-00667-6 kostenfrei https://doaj.org/toc/1758-9193 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2020 1 15
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authorswithroles_txt_mv	Amira Latif-Hernandez @@aut@@ Victor Sabanov @@aut@@ Tariq Ahmed @@aut@@ Katleen Craessaerts @@aut@@ Takashi Saito @@aut@@ Takaomi Saido @@aut@@ Detlef Balschun @@aut@@
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callnumber-first	R - Medicine
author	Amira Latif-Hernandez
spellingShingle	Amira Latif-Hernandez misc RC321-571 misc RC346-429 misc App knock-in mice misc Long-term potentiation misc Long-term depression misc Miniature synaptic currents misc Presynaptic glutamatergic and GABAergic upregulation misc Electrophysiological phenotyping misc Neurosciences. Biological psychiatry. Neuropsychiatry misc Neurology. Diseases of the nervous system The two faces of synaptic failure in App NL-G-F knock-in mice
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topic_title	RC321-571 RC346-429 The two faces of synaptic failure in App NL-G-F knock-in mice App knock-in mice Long-term potentiation Long-term depression Miniature synaptic currents Presynaptic glutamatergic and GABAergic upregulation Electrophysiological phenotyping
topic	misc RC321-571 misc RC346-429 misc App knock-in mice misc Long-term potentiation misc Long-term depression misc Miniature synaptic currents misc Presynaptic glutamatergic and GABAergic upregulation misc Electrophysiological phenotyping misc Neurosciences. Biological psychiatry. Neuropsychiatry misc Neurology. Diseases of the nervous system
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title	The two faces of synaptic failure in App NL-G-F knock-in mice
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title_full	The two faces of synaptic failure in App NL-G-F knock-in mice
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title_sort	two faces of synaptic failure in app nl-g-f knock-in mice
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title_auth	The two faces of synaptic failure in App NL-G-F knock-in mice
abstract	Abstract Background Intensive basic and preclinical research into Alzheimer’s disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in “preclinical AD.” Methods Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in App NL-G-F mice compared to App NL animals which served as controls. Results We found a beginning synaptic impairment (LTP deficit) at 3–4 months in the prefrontal cortex of App NL-G-F mice that is further aggravated and extended to the hippocampus at 6–8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function. Conclusions Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function.
abstractGer	Abstract Background Intensive basic and preclinical research into Alzheimer’s disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in “preclinical AD.” Methods Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in App NL-G-F mice compared to App NL animals which served as controls. Results We found a beginning synaptic impairment (LTP deficit) at 3–4 months in the prefrontal cortex of App NL-G-F mice that is further aggravated and extended to the hippocampus at 6–8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function. Conclusions Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function.
abstract_unstemmed	Abstract Background Intensive basic and preclinical research into Alzheimer’s disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in “preclinical AD.” Methods Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in App NL-G-F mice compared to App NL animals which served as controls. Results We found a beginning synaptic impairment (LTP deficit) at 3–4 months in the prefrontal cortex of App NL-G-F mice that is further aggravated and extended to the hippocampus at 6–8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function. Conclusions Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function.
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title_short	The two faces of synaptic failure in App NL-G-F knock-in mice
url	https://doi.org/10.1186/s13195-020-00667-6 https://doaj.org/article/1e4786f2544f436092354c5f169b3626 http://link.springer.com/article/10.1186/s13195-020-00667-6 https://doaj.org/toc/1758-9193
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One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in “preclinical AD.” Methods Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in App NL-G-F mice compared to App NL animals which served as controls. Results We found a beginning synaptic impairment (LTP deficit) at 3–4 months in the prefrontal cortex of App NL-G-F mice that is further aggravated and extended to the hippocampus at 6–8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function. Conclusions Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">App knock-in mice</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Long-term potentiation</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Long-term depression</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Miniature synaptic currents</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Presynaptic glutamatergic and GABAergic upregulation</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Electrophysiological phenotyping</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Neurosciences. 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The two faces of synaptic failure in App NL-G-F knock-in mice

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