Neurotrophins are key signaling molecules in the development and maintenance of the nervous system. This proposal describes research investigating the function of neurotrophin-3 (NT-3) in the mouse hippocampus and control of NT-3 expression following injury. Studies of expression will utilize a transgenic mouse having the lac Z gene targeted to the NT-3 locus, enabling the location and quantity of NT-3 expression to be easily determined through the use of specific beta- galactosidase substrates. Studies will be performed both in vivo and in vitro to determine the effects of seizure-inducing drugs such as quinolinic and kainic acids on NT-3 levels in distinct parts of the hippocampus and uncover any modulation of these NT-3 responses by specific cytokines and growth factors. Combined X-gal histochemistry and immunocytochemistry will be used to determine the cellular localization of altered NT-3 levels following seizure induction.

The majority of transgenic mice lacking NT-3 die shortly after birth, making it impossible to identify the ultimate consequences of an absence of NT-3 in the CNS. Creation of a conditional NT-3 mutant using the cre- lox system is proposed. The goal of this project is to create mice lacking NT-3 only in the forebrain. These mice are expected to be viable and will be studied for alterations in CNS morphology and behavioral abnormalities. The potent neuronal survival-promoting effect of neurotrophins leads to the testable prediction that these mutant mice will be abnormally susceptible to seizure-induced neurodegeneration.

Elucidation of the functions and regulation of NT-3 in the hippocampus promises to have important clinical and therapeutic implications for human conditions in which hippocampal neurons degenerate, such as epilepsy, stroke, CNS injury and Alzheimer's disease.

K01NS001872

1996-09-27

2001-08-31