? Our working hypothesis is that serotonin (5-HT) receptors are directly responsible for some of the known neuroprotective actions of serotonergic antidepressants in the hippocampus. Our previous studies specifically suggest roles for 5-HT7 and/or 5-HT1A receptors. We have found that 5-HT7 receptors couple to activation of the ERK, Akt, and CREB protective pathways in both cell lines and cultured E18 hippocampal neurons. We have similarly found that 5-HT1 receptors couple to protective pathways in cell lines, though we have not been able to confirm this in E18 hippocampal cultures. The current proposal will further investigate the coupling of 5-HT1A and 5-HTT receptors to ERK, Akt, and CREB in the hippocampus, and directly study neuroprotection. E18 hippocampal neurons will be utilized in Aim 1 to delineate the pathways required for 5-HT receptor-coupling to ERK, Akt, and CREB. The roles of specific cellular components will be identified through the use of selective chemical inhibitors, RNA interference (RNAi), dominant negative constructs, and direct assays of activity. Results from these studies will provide a road map for understanding how alterations in the expression levels or activity of identified pathway components could result in hippocampal pathology.
In Aim 2 we will directly study whether 5- HTT receptor agonists protect hippocampal neurons from apoptosis. E18 hippocampal neurons will be treated with 5-HTT receptor agonists to determine whether they can inhibit the apoptosis induced by two well-studied inducers of apoptosis: 1) nitroprusside (through nitric oxide toxicity) and 2) camptothecin (through DNA damage). Neurons will also be treated with 5-HT7 receptor agonists to determine whether they can inhibit the apoptotic changes induced by agonists for the GR-glucocorticoid receptor. Cultured hippocampal slices from young adult rats will be used in Aim 3 to extend our previous findings in studies designed to determine whether 5-HT_A and 5-HT7 receptors couple to activation of ERK, Akt, and CREB in discrete regions of mature hippocampi. Studies are proposed in Aim 4 to determine the specific roles of 5-HT1A and 5-HT7 receptors in mediating the protective actions of SSRIs observed in animal studies. We propose to perform parallel in vivo and slice culture studies examining the hippocampal effects of 5-HT and selective agonists/antagonists for 5-HT1A and 5-HT7 receptors in stimulating neurogenesis and increasing expression of CREB, BDNF, and TrkB receptors. Slices will be very helpful in interpreting the cause of observed lags in effect since autoreceptors are not present in cultured slices. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH060100-08
Application #
7226228
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Nadler, Laurie S
Project Start
1999-08-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2009-04-30
Support Year
8
Fiscal Year
2007
Total Cost
$298,571
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Psychiatry
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Cowen, Daniel S; Takase, Luiz F; Fornal, Casimir A et al. (2008) Age-dependent decline in hippocampal neurogenesis is not altered by chronic treatment with fluoxetine. Brain Res 1228:14-9
Johnson-Farley, Nadine N; Patel, Khushboo; Kim, Deborah et al. (2007) Interaction of FGF-2 with IGF-1 and BDNF in stimulating Akt, ERK, and neuronal survival in hippocampal cultures. Brain Res 1154:40-9
Cowen, Daniel S (2007) Serotonin and neuronal growth factors - a convergence of signaling pathways. J Neurochem 101:1161-71
Johnson-Farley, Nadine N; Travkina, Tatyana; Cowen, Daniel S (2006) Cumulative activation of akt and consequent inhibition of glycogen synthase kinase-3 by brain-derived neurotrophic factor and insulin-like growth factor-1 in cultured hippocampal neurons. J Pharmacol Exp Ther 316:1062-9
Duann, Pu; Ho, Teh-Yuan; Desai, Bijal D et al. (2005) Mesangial cell apoptosis induced by stimulation of the adenosine A3 receptor: signaling and apoptotic events. J Investig Med 53:37-43
Johnson-Farley, Nadine N; Kertesy, Sylvia B; Dubyak, George R et al. (2005) Enhanced activation of Akt and extracellular-regulated kinase pathways by simultaneous occupancy of Gq-coupled 5-HT2A receptors and Gs-coupled 5-HT7A receptors in PC12 cells. J Neurochem 92:72-82
Cowen, Daniel S; Johnson-Farley, Nadine N; Travkina, Tatyana (2005) 5-HT receptors couple to activation of Akt, but not extracellular-regulated kinase (ERK), in cultured hippocampal neurons. J Neurochem 93:910-7
Lin, Stanley L; Le, Trung X; Cowen, Daniel S (2003) SptP, a Salmonella typhimurium type III-secreted protein, inhibits the mitogen-activated protein kinase pathway by inhibiting Raf activation. Cell Microbiol 5:267-75
Lin, Stanley L; Johnson-Farley, Nadine N; Lubinsky, David R et al. (2003) Coupling of neuronal 5-HT7 receptors to activation of extracellular-regulated kinase through a protein kinase A-independent pathway that can utilize Epac. J Neurochem 87:1076-85
Lin, Stanley L; Setya, Shilpy; Johnson-Farley, Nadine N et al. (2002) Differential coupling of 5-HT(1) receptors to G proteins of the G(i) family. Br J Pharmacol 136:1072-8

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