From organisms using the most basic of nervous systems to the intricate circuits found within the human brain, a fundamental requirement of neuronal function is that it be able to modulate its activity based upon previous experience. In many neurobiological systems, specific patterns of electrical activity will alter the responsiveness of a cell. Long-term changes in cellular excitability due to synaptic stimulation require the synthesis of new protein. This can occur through several mechanisms, including the activation of transcription factors leading to changes in gene expression. Mammalian neurons utilize a variety of second messenger systems sensitive to synaptic stimulation in order to trigger activity-dependent gene expression. Moreover, these signaling proteins regulate many different transcription factors. Using rodent hippocampal neurons, we have been particularly interested in the regulation of cAMP response element binding protein (CREB)- and nuclear factor of activated T-cells (NF-AT)-dependent transcription following brief episodes of heightened synaptic activity, as this is an established model for learning and memory. Under these conditions, both transcription factors are regulated by calcium. Yet remarkably, CREB- and NF-AT-dependent transcription is activated only following the opening of L-type voltage-gated calcium channels. Increases in intracellular calcium via other avenues are ineffective in inducing changes in gene expression. The experiments outlined within this proposal will determine the mechanism by which L-type channels are privileged in signaling to CREB and NF-AT as well as examine the physiological significance for having L-type, and not other calcium entry pathways, responsible for CREB- and NF-AT-dependent transcription. It is our central hypothesis that clustering of L-type channels results in localized calcium signaling within the regions of a neuron containing the signaling machinery responsible for triggering activity-dependent gene expression. Moreover, we believe CREB and NF-AT are differentially regulated by synaptic activity because the second messenger systems responsible for their activation exhibit differences in calcium-sensitivity. Further, we will look to determine the downstream genes being regulated by CREB- and NF-AT-dependent transcription. We will use DNA transfection and manipulation, field stimulation, pharmacology and DNA microarray techniques to achieve our goals. Our results will have implications in clinical disorders arising from dysfunction in activity-dependent gene expression such as Rubenstein-Taybi syndrome, epilepsy and drug addiction, and may help in our understanding of illnesses that result in memory deficits including Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041302-04
Application #
6757209
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Stewart, Randall R
Project Start
2001-07-02
Project End
2005-11-30
Budget Start
2004-07-01
Budget End
2005-11-30
Support Year
4
Fiscal Year
2004
Total Cost
$253,278
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Neurosciences
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Luoma, Jessie I; Stern, Christopher M; Mermelstein, Paul G (2012) Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection. J Steroid Biochem Mol Biol 131:30-6
Mani, S K; Mermelstein, P G; Tetel, M J et al. (2012) Convergence of multiple mechanisms of steroid hormone action. Horm Metab Res 44:569-76
Stern, Christopher M; Meitzen, John; Mermelstein, Paul G (2011) Corticotropin-releasing factor and urocortin I activate CREB through functionally selective Gýýýý signaling in hippocampal pyramidal neurons. Eur J Neurosci 34:671-81
Luoma, Jessie I; Kelley, Brooke G; Mermelstein, Paul G (2011) Progesterone inhibition of voltage-gated calcium channels is a potential neuroprotective mechanism against excitotoxicity. Steroids 76:845-55
Stern, Christopher M; Luoma, Jessie I; Meitzen, John et al. (2011) Corticotropin releasing factor-induced CREB activation in striatal neurons occurs via a novel Gýýýý signaling pathway. PLoS One 6:e18114
Stern, Christopher M (2011) Corticotropin-releasing factor in the hippocampus: eustress or distress? J Neurosci 31:1935-6
Kelley, Brooke G; Mermelstein, Paul G (2011) Progesterone blocks multiple routes of ion flux. Mol Cell Neurosci 48:137-41
Meitzen, John; Luoma, Jessie I; Stern, Christopher M et al. (2011) ?1-Adrenergic receptors activate two distinct signaling pathways in striatal neurons. J Neurochem 116:984-95
Meitzen, John; Mermelstein, Paul G (2011) Estrogen receptors stimulate brain region specific metabotropic glutamate receptors to rapidly initiate signal transduction pathways. J Chem Neuroanat 42:236-41
Meitzen, John; Pflepsen, Kelsey R; Stern, Christopher M et al. (2011) Measurements of neuron soma size and density in rat dorsal striatum, nucleus accumbens core and nucleus accumbens shell: differences between striatal region and brain hemisphere, but not sex. Neurosci Lett 487:177-81

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