Alzheimer's disease (AD) is characterized by excessive cell loss in the hippocampus and several of its afferent pathways, including inputs from the entorhinal cortex (EC), septum/diagonal band and locus coeruleus (LC). In response, the plastic properties of remaining neuronal populations have been reported to be either aberrant or absent, suggesting that the ability of the nervous system to respond to the disease process is impaired. However, the cellular mechanisms that underlie impaired neuronal adaptability in AD are unknown. The studies proposed will address this issue using experimental deafferentation lesions in rats to model the combination of neurotransmitter deficits typically found in AD and investigate the effect of multiple transmitter deficits on reactive synaptogenesis. In addition, we will determine the effect of aging on these processes. For our studies, we will test rats prior to surgery, using the Y maze, to identify subsets of mature (18mo.) and aged (24mo.) rats with hippocampal deficits that may alter their ability to respond to the lesion and the radial arm maze will be used to test rats at various time postlesion to correlate recovery of function with our morphological and molecular parameters. Morphological remodeling of surviving afferent fibers will be evaluated using light microscopic immunocytochemical and histochemical methods. In addition, we will use northern blot and in situ hybridization methods to identify changes in the prevalence of mRNAs of proteins that we hypothesize are associated with the trophic promotion of neurite outgrowth (BDNF), collateral or paraterminal axonal sprouting (GAP-43, SCG-10, P19, NF68), dendrite proliferation (MAP-2) and gap junction formation (Cnx 43 and 32). Data from our studies will provide information which is fundamental to understanding the sequence of morphological and molecular events that characterize reactive synaptogenesis in the dentate gyrus after deafferentation and the effect of aging on these processes. In addition, the information gained will provide insight into how the combined loss of glutamatergic, cholinergic and noradrenergic input to the hippocampus in AD may contribute to the pathophysiology of the disease process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS030426-01
Application #
3417316
Study Section
Special Emphasis Panel (SRC (33))
Project Start
1991-09-30
Project End
1994-09-29
Budget Start
1991-09-30
Budget End
1992-09-29
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Organized Research Units
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Snyder, S E; Cheng, H W; Murray, K D et al. (1998) The messenger RNA encoding VGF, a neuronal peptide precursor, is rapidly regulated in the rat central nervous system by neuronal activity, seizure and lesion. Neuroscience 82:7-19
Snyder, S E; Li, J; Schauwecker, P E et al. (1996) Comparison of RPTP zeta/beta, phosphacan, and trkB mRNA expression in the developing and adult rat nervous system and induction of RPTP zeta/beta and phosphacan mRNA following brain injury. Brain Res Mol Brain Res 40:79-96
Schauwecker, P E; McNeill, T H (1996) Dendritic remodeling of dentate granule cells following a combined entorhinal cortex/fimbria fornix lesion. Exp Neurol 141:145-53
Kohama, S G; Goss, J R; Finch, C E et al. (1995) Increases of glial fibrillary acidic protein in the aging female mouse brain. Neurobiol Aging 16:59-67
Schauwecker, P E; Cheng, H W; Serquinia, R M et al. (1995) Lesion-induced sprouting of commissural/associational axons and induction of GAP-43 mRNA in hilar and CA3 pyramidal neurons in the hippocampus are diminished in aged rats. J Neurosci 15:2462-70
Schauwecker, P E; McNeill, T H (1995) Enhanced but delayed axonal sprouting of the commissural/associational pathway following a combined entorhinal cortex/fimbria fornix lesion. J Comp Neurol 351:453-64
Day, J R; Laping, N J; Lampert-Etchells, M et al. (1993) Gonadal steroids regulate the expression of glial fibrillary acidic protein in the adult male rat hippocampus. Neuroscience 55:435-43
Beck, K D; Lamballe, F; Klein, R et al. (1993) Induction of noncatalytic TrkB neurotrophin receptors during axonal sprouting in the adult hippocampus. J Neurosci 13:4001-14