title: Sex-dependent modulation of age-related cognitive decline by the L-type calcium channel gene Cacna1c (Cav 1.2).
abstract: Increased calcium influx through L-type voltage-gated calcium channels has been implicated in the neuronal dysfunction underlying age-related memory declines. The present study aimed to test the specific role of Cacna1c (which encodes Cav 1.2) in modulating age-related memory dysfunction. Short-term, spatial and contextual/emotional memory was evaluated in young and aged, wild-type as well as mice with one functional copy of Cacna1c (haploinsufficient), using the novel object recognition, Y-maze and passive avoidance tasks, respectively. Hippocampal expression of Cacna1c mRNA was measured by quantitative polymerase chain reaction. Ageing was associated with object recognition and contextual/emotional memory deficits, and a significant increase in hippocampal Cacna1c mRNA expression. Cacna1c haploinsufficiency was associated with decreased Cacna1c mRNA expression in both young and old animals. However, haploinsufficient mice did not manifest an age-related increase in expression of this gene. Behaviourally, Cacna1c haploinsufficiency prevented object recognition deficits during ageing in both male and female mice. A significant correlation between higher Cacna1c levels and decreased object recognition performance was observed in both sexes. Also, a sex-dependent protective role of decreased Cacna1c levels in contextual/emotional memory loss has been observed, specifically in male mice. These data provide evidence for an association between increased hippocampal Cacna1c expression and age-related cognitive decline. Additionally, they indicate an interaction between the Cacna1c gene and sex in the modulation of age-related contextual memory declines.
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, MSTF 936, 685 W. Baltimore Street, Baltimore, MD 21201, USA.
authors.forename: Panos
authors.initials: P
authors.lastname: Zanos
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, MSTF 936, 685 W. Baltimore Street, Baltimore, MD 21201, USA.
authors.forename: Shambhu
authors.initials: S
authors.lastname: Bhat
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, MSTF 936, 685 W. Baltimore Street, Baltimore, MD 21201, USA.
authors.forename: Chantelle E
authors.initials: CE
authors.lastname: Terrillion
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, MSTF 936, 685 W. Baltimore Street, Baltimore, MD 21201, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Smith
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, MSTF 936, 685 W. Baltimore Street, Baltimore, MD 21201, USA.
authors.forename: Leonardo H
authors.initials: LH
authors.lastname: Tonelli
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, MSTF 936, 685 W. Baltimore Street, Baltimore, MD 21201, USA.|Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Gould
mesh_terms: D000375:Aging / Q000502:physiology* / Q000523:psychology*; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000503:physiopathology*; D004644:Emotions / Q000502:physiology; D005260:Female; D057895:Haploinsufficiency; D006624:Hippocampus / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000503:physiopathology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D021641:Recognition, Psychology / Q000502:physiology; D012727:Sex Characteristics; D065852:Spatial Memory / Q000502:physiology
chemical_list: C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D012333:RNA, Messenger
keywords: ageing; cognition; hippocampus; memory; mice