The neurobiological events that underlie learning and memory likely include activity-dependent modification of synaptic strength in brain structures known to subserve memory. Examples of use-dependent synaptic modification hypothesized to contribute to memory are long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission at excitatory synapses in the hippozampus. Hippocampal LTD, similar to hippocampal LTP, is persistent, lasting for days in area CA1 in vivo. The persistence of LTD suggests that the underlying molecular mechanisms involve altered gene expression, although some of the changes in expression must differ from those involved in LTP. The proposed work addresses this issue by examining the role of the serine/threonine protein phosphatases PP1 and PP2A and that of the extracellular signal-regulated kinase (ERK) cascade in LTD and LTP in area CA1 in vivo. Motivated by previous work from our laboratory and work by others, we propose to pursue the following Specific Aims: (1) To determine whether PP1 or PP2A is responsible for decreased activation of the transcription factor CREB during LTD and plays a role in the persistence of LTD; (2) To determine whether LTD requires de novo transcription and translation and is associated with an increase in ERK/Elk-l-mediated gene expression but not in CREB-mediated expression; and (3) To delineate the role of ERK in the regulation of CREB and Elk-1 function in LTD vs. LTP, and test whether reduced phosphatase action on CREB during LTP contributes to the persistence of LTP. We will address these questions with a combination of in vivo electrophysiological techniques, enzyme activity assays, Western blot and immunohistochemical analyses, and in situ hybridization. Collectively, the studies will elucidate mechanisms of negative and positive regulation of transcriptional signals in response to plasticity-inducing synaptic activation in the adult in vivo hippocampus, and will yield models of how interactions among different signaling events combine in the regulation of bidirectional synaptic plasticity. The findings from these studies will provide the foundation for future work directed at relating signaling events involved in bidirectional synaptic plasticity to signaling events involved in different types of memory operations performed by behaving animals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046423-02
Application #
6845727
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Talley, Edmund M
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$269,454
Indirect Cost
Name
University of Pittsburgh
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kotermanski, Shawn E; Johnson, Jon W; Thiels, Edda (2013) Comparison of behavioral effects of the NMDA receptor channel blockers memantine and ketamine in rats. Pharmacol Biochem Behav 109:67-76
Mauna, Jocelyn C; Miyamae, Takeaki; Pulli, Benjamin et al. (2011) Protein phosphatases 1 and 2A are both required for long-term depression and associated dephosphorylation of cAMP response element binding protein in hippocampal area CA1 in vivo. Hippocampus 21:1093-104
Anderson, Warren D; Galván, Emilio J; Mauna, Jocelyn C et al. (2011) Properties and functional implications of I (h) in hippocampal area CA3 interneurons. Pflugers Arch 462:895-912
Yilmaz-Rastoder, Eser; Miyamae, Takeaki; Braun, Amy E et al. (2011) LTP- and LTD-inducing stimulations cause opposite changes in arc/arg3.1 mRNA level in hippocampal area CA1 in vivo. Hippocampus 21:1290-301
Galvan, Emilio J; Cosgrove, Kathleen E; Mauna, Jocelyn C et al. (2010) Critical involvement of postsynaptic protein kinase activation in long-term potentiation at hippocampal mossy fiber synapses on CA3 interneurons. J Neurosci 30:2844-55
Shiflett, Michael W; Mauna, Jocelyn C; Chipman, Amanda M et al. (2009) Appetitive Pavlovian conditioned stimuli increase CREB phosphorylation in the nucleus accumbens. Neurobiol Learn Mem 92:451-4
Shiflett, Michael W; Martini, Ross P; Mauna, Jocelyn C et al. (2008) Cue-elicited reward-seeking requires extracellular signal-regulated kinase activation in the nucleus accumbens. J Neurosci 28:1434-43
Hu, Daoying; Klann, Eric; Thiels, Edda (2007) Superoxide dismutase and hippocampal function: age and isozyme matter. Antioxid Redox Signal 9:201-10