title: The L-type calcium channel Cav1.3 is required for proper hippocampal neurogenesis and cognitive functions.
abstract: L-type voltage gated Ca(2+) channels (LTCCs) are widely expressed within different brain regions including the hippocampus. The isoforms Cav1.2 and Cav1.3 have been shown to be involved in hippocampus-dependent learning and memory, cognitive functions that require proper hippocampal neurogenesis. In vitro, functional LTCCs are expressed on neuronal progenitor cells, where they promote neuronal differentiation. Expression of LTCCs on neural stem and progenitor cells within the neurogenic regions in the adult brain in vivo has not been examined so far, and a contribution of the individual isoforms Cav1.2 and Cav1.3 to adult neurogenesis remained to be clarified. To reveal the role of these channels we first evaluated the expression patterns of Cav1.2 and Cav1.3 in the hippocampal dentate gyrus and the subventricular zone (SVZ) in adult (2- and 3-month old) and middle-aged (15-month old) mice on mRNA and protein levels. We performed immunohistological analysis of hippocampal neurogenesis in adult and middle-aged Cav1.3(-/-) mice and finally addressed the importance of Cav1.3 for hippocampal function by evaluating spatial memory and depression-like behavior in adult Cav1.3(-/-) mice. Our results showed Cav1.2 and Cav1.3 expression at different stages of neuronal differentiation. While Cav1.2 was primarily restricted to mature NeuN(+) granular neurons, Cav1.3 was expressed in Nestin(+) neural stem cells and in mature NeuN(+) granular neurons. Adult and middle-aged Cav1.3(-/-) mice showed severe impairments in dentate gyrus neurogenesis, with significantly smaller dentate gyrus volume, reduced survival of newly generated cells, and reduced neuronal differentiation. Further, Cav1.3(-/-) mice showed impairment in the hippocampus dependent object location memory test, implicating Cav1.3 as an essential element for hippocampus-associated cognitive functions. Thus, modulation of LTCC activities may have a crucial impact on neurogenic responses and cognition, which should be considered for future therapeutic administration of LTCCs modulators.
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Marschallinger
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens-University of Innsbruck, Innsbruck, Austria.
authors.forename: Anupam
authors.initials: A
authors.lastname: Sah
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens-University of Innsbruck, Innsbruck, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schmuckermair
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Unger
authors.affiliation: Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria; Institute of Experimental Neuroregeneration, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Rotheneichner
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens-University of Innsbruck, Innsbruck, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Kharitonova
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Waclawiczek
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria.
authors.forename: Philipp
authors.initials: P
authors.lastname: Gerner
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria.
authors.forename: Heidi
authors.initials: H
authors.lastname: Jaksch-Bogensperger
authors.affiliation: Department of Molecular Biology, Central Institute of Mental Health and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Berger
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens-University of Innsbruck, Innsbruck, Austria.
authors.forename: Jörg
authors.initials: J
authors.lastname: Striessnig
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and CMBI, Leopold-Franzens-University of Innsbruck, Innsbruck, Austria.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Singewald
authors.affiliation: Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria; Institute of Experimental Neuroregeneration, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Couillard-Despres
authors.affiliation: Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria. Electronic address: ludwig.aigner@pmu.ac.at.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Aigner
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D003071:Cognition / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism*; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*
chemical_list: C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type
keywords: Adult neurogenesis; Cacna1d; Calcium channels; Cognition; Neuronal differentiation