AGE-RELATED LOSS OF CHOLINERGIC-MUSCARINIC COUPLING TO PLC - COMPARISON WITH CHANGES IN BRAIN REGIONAL PLC SUBTYPES MESSENGER-RNA DISTRIBUTION

Activation of phospholipase C (PLC) coupled to phosphoinositide (PtdIn s) hydrolysis occurs through one of the two pathways. One of the major pathways for the neurotransmitter signaling involves phosphoinositide (PtdIns) specific and G-protein dependent PLC-beta, which stimulates the formation of inositol triphosphate (IP3) and inositol tetraphospha te (IP4). Another pathway through the stimulation of calcium influx ca n directly activate all of the PLC isozymes. At least three isozymes o f PLC have been characterized in the brain; PLC-A (alpha), PLC-I (beta ) and PLC-II (gamma), which are shown to be localized differentially i n brain regions. Muscarinic-cholinergic signals are mediated in large part through the hydrolysis of PtdIns by PLC. To investigate changes i n muscarinic coupling to PLC during aging, we examined carbachol stimu lated and calcium stimulated PtdIns hydrolysis in cerebral cortical me mbranes in young, middle aged and old rats. In order to determine whet her PtdIns hydrolysis changes correspond to PLC isozyme expression in these animals, we examined three subtypes of PLC mRNA expression in br ain sections of young and old rats using in situ hybridization techniq ue. Our study indicated decreased carbachol-induced PLC activity in th e cerebral cortex and, in contrast, increased PLC-beta mRNA in the fro ntal cortex and superficial cortical layer of aged rats. PLC-alpha mRN A was decreased in hippocampal regions of older rats. These studies su ggest that during aging there is an uncoupling of muscarinic stimulate d PtdIns hydrolysis, which is accompanied by an increased PLC-beta mRN A and decreased PLC-alpha mRNA that may represent compensatory changes in PLC expression.