Metabotropic Acetylcholine and Glutamate Receptors Mediate PI(4,5)P(2) Depletion and Oscillations in Hippocampal CA1 Pyramidal Neurons in situ

The sensitivity of many ion channels to phosphatidylinositol-4,5-bisphosphate (PIP(2)) levels in the cell membrane suggests that PIP(2) fluctuations are important and general signals modulating neuronal excitability. Yet the PIP(2) dynamics of central neurons in their native environment remained largely unexplored. Here, we examined the behavior of PIP(2) concentrations in response to activation of Gq-coupled neurotransmitter receptors in rat CA1 hippocampal neurons in situ in acute brain slices. Confocal microscopy of the PIP(2)-selective molecular sensors tubby(CT)-GFP and PLCδ1-PH-GFP showed that pharmacological activation of muscarinic acetylcholine (mAChR) or group I metabotropic glutamate (mGluRI) receptors induces transient depletion of PIP(2) in the soma as well as in the dendritic tree. The observed PIP(2) dynamics were receptor-specific, with mAChR activation inducing stronger PIP(2) depletion than mGluRI, whereas agonists of other Gα(q)-coupled receptors expressed in CA1 neurons did not induce measureable PIP(2) depletion. Furthermore, the data show for the first time neuronal receptor-induced oscillations of membrane PIP(2) concentrations. Oscillatory behavior indicated that neurons can rapidly restore PIP(2) levels during persistent activation of Gq and PLC. Electrophysiological responses to receptor activation resembled PIP(2) dynamics in terms of time course and receptor specificity. Our findings support a physiological function of PIP(2) in regulating electrical activity.