Advancing age is often accompanied by cognitive impairments characterized by substantial deficits in learning and memory. These deficits adversely effect day to day living, reduce the quality of life and impose a financial and social burden on the affected and their families. The exact neuronal mechanism that gives rise to these age-related impairments remains unknown. However, data from experiments using a variety of model systems, suggests that dysregulation of neuronal Ca2+ homeostasis is a significant contributing factor to these cognitive impairments. Specifically, there appears to be an age-related increase in intracellular calcium [Ca2+]i in neurons observed during neuronal activity. This increase in activity-driven accumulation of [Ca2+]i adversely impacts neuronal excitability and long-term potentiation (LTP), processes that have both been implicated in learning &memory. It has been suggested that the increase in [Ca2+]i is the result of an age-related increase in expression of L-type voltage-gated calcium channels (L-VGCCs). This has led to the hypothesis that an age-related increase in L-VGCCs expression leads to a decrease in neuronal excitability which in turn reduces LTP. The resulting decrease in LTP disrupts the ability of the hippocampus to encode new information. In this proposal we will use a multidisciplinary approach to test key elements of this hypothesis.
In Specific Aim I we will use L-VGCC knockout (KO) mice to determine whether L-VGCCs are necessary for the age-related decrease in neuronal excitability and LTP.
In Specific Aim II, using organotypic hippocampal slice cultures and epitope-tagged recombinant L-VGCC pore forming subunits, we will determine whether over-expression of L-VGCCs is sufficient to produce changes in neuronal excitability and LTP similar to that observed during normal aging. Finally, in Specific Aim III we will utilize L-VGCC KO mice to determine to what extent L-VGCCs contribute to the learning &memory deficits normally observed in aged mice. Results from these studies will provide us with valuable insights into the neurobiology of aging and will aid in the identification of targets for the therapeutic intervention, designed to ameliorate cognitive impairments that arise from alterations in age-related calcium homeostasis.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Wagster, Molly V
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
Krueger, Jamie N; Moore, Shannon J; Parent, Rachel et al. (2017) A novel mouse model of the aged brain: Over-expression of the L-type voltage-gated calcium channel CaV1.3. Behav Brain Res 322:241-249
Temme, Stephanie J; Murphy, Geoffrey G (2017) The L-type voltage-gated calcium channel CaV1.2 mediates fear extinction and modulates synaptic tone in the lateral amygdala. Learn Mem 24:580-588
Patriarchi, Tommaso; Qian, Hai; Di Biase, Valentina et al. (2016) Phosphorylation of Cav1.2 on S1928 uncouples the L-type Ca2+ channel from the ?2 adrenergic receptor. EMBO J 35:1330-45
Temme, Stephanie J; Bell, Ryan Z; Fisher, Grace L et al. (2016) Deletion of the Mouse Homolog of CACNA1C Disrupts Discrete Forms of Hippocampal-Dependent Memory and Neurogenesis within the Dentate Gyrus. eNeuro 3:
Su, Enming J; Fredriksson, Linda; Kanzawa, Mia et al. (2015) Imatinib treatment reduces brain injury in a murine model of traumatic brain injury. Front Cell Neurosci 9:385
Berkowitz, Bruce A; Murphy, Geoffrey G; Craft, Cheryl Mae et al. (2015) Genetic dissection of horizontal cell inhibitory signaling in mice in complete darkness in vivo. Invest Ophthalmol Vis Sci 56:3132-9
Fredriksson, Linda; Stevenson, Tamara K; Su, Enming J et al. (2015) Identification of a neurovascular signaling pathway regulating seizures in mice. Ann Clin Transl Neurol 2:722-38
Renoux, A J; Sala-Hamrick, K J; Carducci, N M et al. (2014) Impaired sensorimotor gating in Fmr1 knock out and Fragile X premutation model mice. Behav Brain Res 267:42-5
Moore, Shannon J; Deshpande, Kaivalya; Stinnett, Gwen S et al. (2013) Conversion of short-term to long-term memory in the novel object recognition paradigm. Neurobiol Learn Mem 105:174-85
Singer, Benjamin H; Gamelli, Amy E; Fuller, Cynthia L et al. (2011) Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young-adult mice. Proc Natl Acad Sci U S A 108:5437-42

Showing the most recent 10 out of 14 publications