TARGET-DERIVED NEURONOTROPHIC FACTORS

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Nerve growth factor is a target-derived protein for the peripheral sympathetic and sensory nervous system. Similar trophic factors have been postulated to exist for central nervous system neurons. The identification of a neurotrophic factor involved in the cholinergic septo-hippocampal pathway is the subject of this research project. Conventional and molecular biological approaches to this problem have been initiated. Primary dissociated cultures of rat fetal septal area neurons have been established as an assay system to monitor the activity of the cholinergic trophic factor. These cultured cells have an uptake system for choline that is time-, temperature-, and partially Na-dependent. Preliminary results also show that acetylcholine is synthesized from the choline taken up by the cells. Thus, septal cells in culture are a suitable system to assay for cholinergic trophic factor(s) that may be induced by lesions of the septo-hippocampal pathway. A molecular biological approach is also being used to identify and, ultimately, characterize the trophic factor. Complementary DNA (cDNA) has been synthesized from hippocampal mRNA and will be used in cDNA-mRNA hybridizations to identify lesion-induced and novel mRNA species. Injection of frog oocytes with mRNA fractions will serve as an in vitro translation system and the encoded trophic proteins will be assayed by alterations in the cholinergic parameters of the cultured septal cells. Identification and cloning of a novel cholinergic neuronotrophic factor may lead to new therapeutic approaches to neurological diseases with an altered cholinergic component, such as Alzheimer's disease.