The broad aim of this proposal is to understand the electrophysiological consequence of polyphosphatidylinositol (PPI) turnover in mammalian central neurons. It has become clear that the hydrolysis of membrane inositol phospholipids is an important component of signal transduction for many neurotransmitters. It is implicated in secretion and muscle contraction and may initiate relatively long term effects such as growth and memory. Most Of our knowledge of the PPI system and its significance comes from non-neuronal cells, yet the brain has the highest levels of the receptors for the second messengers produced. The PPI system is composed of two major branches. This proposal will focus on the inositol phosphate limb, since there is almost nothing known of the effects of the inositol phosphates in mammalian central neurons. Preliminary studies with inositol trisphosphates indicate that they exert dramatic inhibitory influences on neuronal excitability, apparently activating two distinct potassium-dependent afterhyperpolarizations. Similar afterhyperpolarizations seen in normal cells function to limit burst duration and repetitive firing. Thus, inositol phosphates may play an important regulatory role in neuronal communication, particularly in epilepsy and memory. The rodent hippocampal slice will be used as a model system to investigate the neurophysiology of the inositol phosphates by studying the activity of single neurons. A unique strength of this proposal is that metabolically stable analogues of the inositol phosphates, as well as the natural compounds, will be utilized. Thus, ambiguities related to metabolism are avoided and observed actions can be ascribed to a specific inositol phosphate. The effects of applied inositol phosphates will be related to the actions of neurotransmitters thought to be coupled to PPI. At present, there are few cases in central neurons in which particular electro- physiological effects of neurotransmitters have been attributed to these second messengers. The influence of inositol phosphates on neuronal activity thought to be important in epilepsy and memory will also be evaluated. The studies proposed can advance our understanding of the neuronal PPI system by identifying electrophysiological consequences of increases in inositol phosphates. As alterations in PPI metabolism have been found in epilepsy and memory models, the hippocampus is particularly relevant for studies of this kind, as it is a structure thought to play an important role in these neuronal activities.
