Our previous work indicates that protein phosphatase activity is increased in hippocampus of aged rats and contributes to age-related alterations in synaptic strength and cognition. The proposed studies investigate whether the protein phosphatase calcineurin interacts significantly with several other brain aging biomarkers, including increased Ca2+ channel function and altered gene expression. In each aim of this project, calcineurin activity in hippocampal cultures and in hippocampus of intact rats, is manipulated using recombinant viruses (adeno- and lentivirus). The first specific aim tests whether constitutively active calcineurin causes aging-like changes in voltage sensitive Ca2+ channels (VSCC) (i.e. an increase in L-type VSCC currents and a decrease in N-type VSCC mRNA levels). Molecular interactions of calcineurin with VSCCs also will be explored.
The second aim tests whether increased calcineurin activity leads to aging-like changes in global gene expression, as assessed using gene microarrays. The specific role of the calcineurin/NF-AT transcriptional pathway will be explored using recombinant virus containing a potent NFAT inhibitor, VIVIT.
The third aim uses recombinant viruses to test whether the calcineurin/NF-AT pathway contributes to age-related memory deficits on the Morris swim task. After completion of behavioral training, intact and partially dissociated hippocampal slices will be prepared from these rats to determine whether the calcineurin/NF-AT pathway also is responsible, in part, for age-related alterations in synaptic strength, plasticity (i.e. long-term potentiation and long-term depression), and L-type VSCC activity. Furthermore, individual neurons and glia will be harvested from zipper slices to examine single cell gene expression profiles using gene microarray technology.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AG024190-03
Application #
7110134
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Wise, Bradley C
Project Start
2004-09-30
Project End
2009-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
3
Fiscal Year
2006
Total Cost
$85,933
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Castonguay, David; Dufort-Gervais, Julien; Ménard, Caroline et al. (2018) The Tyrosine Phosphatase STEP Is Involved in Age-Related Memory Decline. Curr Biol 28:1079-1089.e4
Sama, Diana M; Norris, Christopher M (2013) Calcium dysregulation and neuroinflammation: discrete and integrated mechanisms for age-related synaptic dysfunction. Ageing Res Rev 12:982-95
Sama, Diana M; Mohmmad Abdul, Hafiz; Furman, Jennifer L et al. (2012) Inhibition of soluble tumor necrosis factor ameliorates synaptic alterations and Ca2+ dysregulation in aged rats. PLoS One 7:e38170
Mohmmad Abdul, Hafiz; Baig, Irfan; Levine 3rd, Harry et al. (2011) Proteolysis of calcineurin is increased in human hippocampus during mild cognitive impairment and is stimulated by oligomeric Abeta in primary cell culture. Aging Cell 10:103-13
Furman, Jennifer L; Artiushin, Irina A; Norris, Christopher M (2010) Disparate effects of serum on basal and evoked NFAT activity in primary astrocyte cultures. Neurosci Lett 469:365-9
Norris, Christopher M; Blalock, Eric M; Chen, Kuey-Chu et al. (2010) Hippocampal 'zipper' slice studies reveal a necessary role for calcineurin in the increased activity of L-type Ca(2+) channels with aging. Neurobiol Aging 31:328-38
Abdul, Hafiz Mohmmad; Furman, Jennifer L; Sama, Michelle A et al. (2010) NFATs and Alzheimer's Disease. Mol Cell Pharmacol 2:7-14
Abdul, Hafiz Mohmmad; Sama, Michelle A; Furman, Jennifer L et al. (2009) Cognitive decline in Alzheimer's disease is associated with selective changes in calcineurin/NFAT signaling. J Neurosci 29:12957-69
Sama, Michelle A; Mathis, Diana M; Furman, Jennifer L et al. (2008) Interleukin-1beta-dependent signaling between astrocytes and neurons depends critically on astrocytic calcineurin/NFAT activity. J Biol Chem 283:21953-64
Jeftinija, Dusan M; Wang, Qing Bo; Hebert, Sadie L et al. (2007) The Ca(V) 1.2 Ca(2+) channel is expressed in sarcolemma of type I and IIa myofibers of adult skeletal muscle. Muscle Nerve 36:482-90

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