EFFECT OF HIPPOCAMPAL SYMPATHETIC INGROWTH AND CHOLINERGIC DENERVATION ON HIPPOCAMPAL PHOSPHOLIPASE-C ACTIVITY AND G-PROTEIN FUNCTION

Following cholinergic denervation of the hippocampal formation, via me dial septal lesions, peripheral noradrenergic fibers, originating from the superior cervical ganglion, grow into the hippocampus. In previou s studies, we have found that hippocampal sympathetic ingrowth and cho linergic denervation alone (animals with concurrent medial septal lesi ons and superior cervical ganglionectomy) alter phosphoinositide turno ver and muscarinic cholinergic receptors in such a way as to suggest a n alteration in coupling between the muscarinic cholinergic receptors and phosphoinositol turnover. To test this hypothesis we examined the effect of hippocampal sympathetic ingrowth and cholinergic denervation on phospholipase C activity, G-protein function and the whole recepto r complex by measuring the amount of phosphoinositide hydrolysed in hi ppocampal membranes of the rat. Neither hippocampal sympathetic ingrow th nor cholinergic denervation was found to alter phospholipase C acti vity when activated by increasing concentrations of Ca2+. In dorsal hi ppocampus, cholinergic denervation, when compared to hippocampal sympa thetic ingrowth and controls, was found to decrease the amount of phos phoinositol hydrolysed when stimulated with the GTP analog, guanosine- 5'-O-(3-thiotriphosphate). When guanosine-5'-O-(3-thiotriphosphate) pl us carbachol (1 mM) was utilized to stimulate the entire receptor comp lex, phosphoinositol hydrolysis was found to be decreased in the choli nergic denervation group as compared to both hippocampal sympathetic i ngrowth and control groups. This effect was maximum at 3 mu M guanosin e-5'-O-(3-thiotriphosphate).These results suggest that both hippocampa l sympathetic ingrowth and cholinergic denervation affect the efficien cy of coupling between the muscarinic cholinergic receptors and phosph oinositol turnover, with cholinergic denervation decreasing and hippoc ampal sympathetic ingrowth ''normalizing'' efficiency. Further, they s uggest that the G-protein is the site at which hippocampal sympathetic ingrowth and cholinergic denervation mediate their effects. The resul ts of these experiments are also discussed within the context of recen t findings demonstrating G-protein abnormalities in Alzheimer's diseas e. Copyright (C) 1997 IBRO.