This proposal has 2 well defined goals: to explore the consequences of administering GM1 ganglioside on brain neurotransmission in aged rats, and to determine the mechanism(s) for the trophic action of GM1 in vivo. The main focus will be on the dopaminergic system. Systemic administration of GM1, a normal constituent of the membranes of brain, was previously shown to enhance cholinergic neurochemical and morphological markers in the brain of aged rats.
The first aim i s to determine the effects of GM1 on dopaminergic neurochemical deficits in the brain of aged animals, and evaluate whether the response is stable when treatment is discontinued. This includes the following: to elucidate whether cholinergic and dopaminergic function that deteriorates with age can be prevented or delayed by administering GM1 to mature animals; to study by immunohistochemistry-autoradiography whether GM1 improves the number and/or morphology of the neurons of interest, and whether GM1 can induce neuronal sprouting; to dissect the possible relationship between the various neurotransmitter deficits and cognitive and motor function in aged animals; to explore whether enhancement of neurochemical and morphological markers by GM1 includes behavioral (cognitive, motor) improvement and investigate the possible relationship(s) with specific neurotransmitter change(s). The second specific aim is to establish the mechanism(s) for the trophic action of GM1 in the brain in vivo. This includes the following: to establish an in situ system to investigate the GM1-induced tyrosine phosphorylation of Trk in brain slices from young and aged animals; to determine the pharmacology and specificity of the response; to determine whether the GM1-induced tyrosine phosphorylation of Trk initiates the same signal cascade as the neurotrophins; to explore the GM1/ neurotrophin synergism at the molecular level. To investigate whether acute or chronic administration of GM1 induces tyrosine phosphorylation of Trk in vivo, the possible enhancement of the neurotrophin-induced autophosphorylation of Trk, and the effect of aging on the response(s).
| Farooqui, T; Yates, A J (1998) Effect of GM1 on TrkA dimerization. Ann N Y Acad Sci 845:407 |
