title: Ablation of Ca(V)2.1 voltage-gated Ca²⁺ channels in mouse forebrain generates multiple cognitive impairments.
abstract: 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.
authors.affiliation: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität, Freiburg, Germany ; Fakultät für Biologie, Albert-Ludwigs-Universität, Freiburg, Germany.
authors.forename: Robert Theodor
authors.initials: RT
authors.lastname: Mallmann
authors.forename: Claudio
authors.initials: C
authors.lastname: Elgueta
authors.forename: Faten
authors.initials: F
authors.lastname: Sleman
authors.forename: Jan
authors.initials: J
authors.lastname: Castonguay
authors.forename: Thomas
authors.initials: T
authors.lastname: Wilmes
authors.forename: Arn
authors.initials: A
authors.lastname: van den Maagdenberg
authors.forename: Norbert
authors.initials: N
authors.lastname: Klugbauer
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000172:deficiency* / Q000235:genetics*; D003071:Cognition / Q000502:physiology*; D055786:Gene Knockout Techniques; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D016548:Prosencephalon / Q000378:metabolism*; D021641:Recognition, Psychology / Q000502:physiology
chemical_list: D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C)