Uncoupling of muscarinic cholinergic phosphoinositide signals in senescent cerebral cortical and hippocampal membranes

Abstract

Muscarinic-cholinergic signals in brain are mediated in part through the hydrolysis of phosphoinositides (PtdIns) by phospholipase C (PLC). To test the hypothesis that muscarinic PtdIns signals change during aging, membranes were prepared from the cerebral cortex and hippocampus of young (4–6 months old), middle aged (8–10 months old) and senescent (24–26 months old) Fisher 344 rats. Carbachol dose-dependently increased [ 3H]-PtdIns hydrolysis in both brain regions in all three age groups, however, in senescent rats the maximal response was decreased to 69.26 ± 4.33% ( p < 0.01) in cortex and to 48.29 ± 2.55% ( p < 0.01) in hippocampus of young rat values. In contrast to the decrease in carbachol-stimulated phosphoinositide hydrolysis, calcium-stimulated phosphoinositide hydrolysis was not altered. GTPγS also dose-dependently increased [ 3H]-PtdIns hydrolysis in membranes from all three age groups through G-protein-PLC activation. Similar to carbachol, GTPγS-activated [ 3H]-PtdIns hydrolysis was reduced approximately 40% in senescent rats membranes. Muscarinic receptor (mAChR) density, as determined by [ 3H]-QNB binding decreased slightly in cortical membranes, but not in hippocampal membranes. These data suggest that muscarinic stimulated [ 3H]-PtdIns responses are decreased in senescent brain primarily due to an uncoupling of the receptor-G-protein and/or G-protein-PLC link, although decreases in receptor density may also contribute to reduced muscarinic [ 3H]-PtdIns signaling.