An age-dependent decline in serotonergic innervation of the forebrain has been well documented and may contribute to late onset neurodegenerative disorders, increased incidence of depression or loss of cognitive function that occur with age in humans. This proposal will investigate the relationship between long-term elevations in synaptic serotonin and age and their effects on neuronal innervation in mice with a genetic inactivation of the serotonin transporter gene. Our recent studies indicate that decreased serotonin transporter expression results in a reversal or prevention of normal age-related degeneration of serotonergic axons. We hypothesize that increased extracellular serotonin may be functioning as a trophic factor to promote the survival of serotonergic axons in the forebrain. Mice that lack the serotonin transporter display a 5-fold increase in extracellular serotonin compared to wild type mice. In mice with a 50% reduction in serotonin transporter expression, a 5-fold increase in extracellular serotonin has been detected. In fact, 70% of the normal human population expresses approximately 30% less serotonin transporter, so these findings will have direct applicability to aging in humans. We will investigate the effect decreased serotonin transporter expression on the survival and integrity of forebrain serotonergic, catecholaminergic and cholinergic axons by immunocytochemistry. In addition, we will evaluate the age-related effects of reduced serotonin transporter expression on regional serotonin, dopamine, norepinephrine and acetylcholine neurotransmitter levels. These studies have been designed to integrate anatomical and neurochemical data to assess age-related changes in axonal innervation across the lifespan resulting from decreased of the serotonin transporter expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Small Research Grants (R03)
Project #
1R03MH067713-01
Application #
6598972
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Brady, Linda S
Project Start
2003-04-11
Project End
2005-03-31
Budget Start
2003-04-11
Budget End
2004-03-31
Support Year
1
Fiscal Year
2003
Total Cost
$66,792
Indirect Cost
Name
Pennsylvania State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Luellen, B A; Bianco, L E; Schneider, L M et al. (2007) Reduced brain-derived neurotrophic factor is associated with a loss of serotonergic innervation in the hippocampus of aging mice. Genes Brain Behav 6:482-90
Luellen, Beth A; Szapacs, Matthew E; Materese, Christopher K et al. (2006) The neurotoxin 2'-NH2-MPTP degenerates serotonin axons and evokes increases in hippocampal BDNF. Neuropharmacology 50:297-308
Szapacs, Matthew E; Mathews, Tiffany A; Tessarollo, Lino et al. (2004) Exploring the relationship between serotonin and brain-derived neurotrophic factor: analysis of BDNF protein and extraneuronal 5-HT in mice with reduced serotonin transporter or BDNF expression. J Neurosci Methods 140:81-92
Mathews, Tiffany A; Fedele, Denise E; Coppelli, Francesca M et al. (2004) Gene dose-dependent alterations in extraneuronal serotonin but not dopamine in mice with reduced serotonin transporter expression. J Neurosci Methods 140:169-81
Szapacs, Matthew E; Numis, Adam L; Andrews, Anne M (2004) Late onset loss of hippocampal 5-HT and NE is accompanied by increases in BDNF protein expression in mice co-expressing mutant APP and PS1. Neurobiol Dis 16:572-80
Luellen, Beth A; Miller, Diane B; Chisnell, Angela C et al. (2003) Neuronal and astroglial responses to the serotonin and norepinephrine neurotoxin: 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine. J Pharmacol Exp Ther 307:923-31