Ablation of Ca(V)2.1 voltage-gated Ca²⁺ channels in mouse forebrain generates multiple cognitive impairments.

Voltage-gated Ca(V)2.1 (P/Q-type) Ca²⁺ channels located at the presynaptic membrane are known to control a multitude of Ca²⁺-dependent cellular processes such as neurotransmitter release and synaptic plasticity. Our knowledge about their contributions to complex cognitive functions, however, is rest...

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Main Authors: Robert Theodor Mallmann, Claudio Elgueta, Faten Sleman, Jan Castonguay, Thomas Wilmes, Arn van den Maagdenberg, Norbert Klugbauer
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2013-01-01
Series:PLoS ONE
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24205277/pdf/?tool=EBI
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spelling doaj-04567f69fe074b20ba9c52c3529e89ad2021-03-03T22:47:31ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01810e7859810.1371/journal.pone.0078598Ablation of Ca(V)2.1 voltage-gated Ca²⁺ channels in mouse forebrain generates multiple cognitive impairments.Robert Theodor MallmannClaudio ElguetaFaten SlemanJan CastonguayThomas WilmesArn van den MaagdenbergNorbert KlugbauerVoltage-gated Ca(V)2.1 (P/Q-type) Ca²⁺ channels located at the presynaptic membrane are known to control a multitude of Ca²⁺-dependent cellular processes such as neurotransmitter release and synaptic plasticity. Our knowledge about their contributions to complex cognitive functions, however, is restricted by the limited adequacy of existing transgenic Ca(V)2.1 mouse models. Global Ca(V)2.1 knock-out mice lacking the α1 subunit Cacna1a gene product exhibit early postnatal lethality which makes them unsuitable to analyse the relevance of Ca(V)2.1 Ca²⁺ channels for complex behaviour in adult mice. Consequently we established a forebrain specific Ca(V)2.1 knock-out model by crossing mice with a floxed Cacna1a gene with mice expressing Cre-recombinase under the control of the NEX promoter. This novel mouse model enabled us to investigate the contribution of Ca(V)2.1 to complex cognitive functions, particularly learning and memory. Electrophysiological analysis allowed us to test the specificity of our conditional knock-out model and revealed an impaired synaptic transmission at hippocampal glutamatergic synapses. At the behavioural level, the forebrain-specific Ca(V)2.1 knock-out resulted in deficits in spatial learning and reference memory, reduced recognition memory, increased exploratory behaviour and a strong attenuation of circadian rhythmicity. In summary, we present a novel conditional Ca(V)2.1 knock-out model that is most suitable for analysing the in vivo functions of Ca(V)2.1 in the adult murine forebrain.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24205277/pdf/?tool=EBI
collection DOAJ
language English
format Article
sources DOAJ
author Robert Theodor Mallmann
Claudio Elgueta
Faten Sleman
Jan Castonguay
Thomas Wilmes
Arn van den Maagdenberg
Norbert Klugbauer
spellingShingle Robert Theodor Mallmann
Claudio Elgueta
Faten Sleman
Jan Castonguay
Thomas Wilmes
Arn van den Maagdenberg
Norbert Klugbauer
Ablation of Ca(V)2.1 voltage-gated Ca²⁺ channels in mouse forebrain generates multiple cognitive impairments.
PLoS ONE
author_facet Robert Theodor Mallmann
Claudio Elgueta
Faten Sleman
Jan Castonguay
Thomas Wilmes
Arn van den Maagdenberg
Norbert Klugbauer
author_sort Robert Theodor Mallmann
title Ablation of Ca(V)2.1 voltage-gated Ca²⁺ channels in mouse forebrain generates multiple cognitive impairments.
title_short Ablation of Ca(V)2.1 voltage-gated Ca²⁺ channels in mouse forebrain generates multiple cognitive impairments.
title_full Ablation of Ca(V)2.1 voltage-gated Ca²⁺ channels in mouse forebrain generates multiple cognitive impairments.
title_fullStr Ablation of Ca(V)2.1 voltage-gated Ca²⁺ channels in mouse forebrain generates multiple cognitive impairments.
title_full_unstemmed Ablation of Ca(V)2.1 voltage-gated Ca²⁺ channels in mouse forebrain generates multiple cognitive impairments.
title_sort ablation of ca(v)2.1 voltage-gated ca²⁺ channels in mouse forebrain generates multiple cognitive impairments.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2013-01-01
description Voltage-gated Ca(V)2.1 (P/Q-type) Ca²⁺ channels located at the presynaptic membrane are known to control a multitude of Ca²⁺-dependent cellular processes such as neurotransmitter release and synaptic plasticity. Our knowledge about their contributions to complex cognitive functions, however, is restricted by the limited adequacy of existing transgenic Ca(V)2.1 mouse models. Global Ca(V)2.1 knock-out mice lacking the α1 subunit Cacna1a gene product exhibit early postnatal lethality which makes them unsuitable to analyse the relevance of Ca(V)2.1 Ca²⁺ channels for complex behaviour in adult mice. Consequently we established a forebrain specific Ca(V)2.1 knock-out model by crossing mice with a floxed Cacna1a gene with mice expressing Cre-recombinase under the control of the NEX promoter. This novel mouse model enabled us to investigate the contribution of Ca(V)2.1 to complex cognitive functions, particularly learning and memory. Electrophysiological analysis allowed us to test the specificity of our conditional knock-out model and revealed an impaired synaptic transmission at hippocampal glutamatergic synapses. At the behavioural level, the forebrain-specific Ca(V)2.1 knock-out resulted in deficits in spatial learning and reference memory, reduced recognition memory, increased exploratory behaviour and a strong attenuation of circadian rhythmicity. In summary, we present a novel conditional Ca(V)2.1 knock-out model that is most suitable for analysing the in vivo functions of Ca(V)2.1 in the adult murine forebrain.
url https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24205277/pdf/?tool=EBI
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