Polyphosphoinositol lipids: under-PPInning synaptic function in health and disease

Phosphoinositides (PPIn) form a unique family of lipids derived by phosphorylation of the parent compound, phosphatidylinositol. Despite being minor constituents of synaptic membranes, these lipids have exceptionally high rates of metabolic turnover and are involved with myriad aspects of pre- and post-synaptic function, from the control of the synaptic vesicle cycle to postsynaptic excitability. In this review, we outline the main synaptic processes known to be regulated by these molecules, focusing mainly but not exclusively on the major species phosphatidylinositol 4-phosphate and phosphatidylinositol (4,5)-bisphosphate. Furthermore, we discuss the enzymes responsible for their synthesis and degradation, with a view to exploring how the activity-dependent control of their enzymatic action can lead to the precise regulation of PPIn levels at the nerve terminal. Also, the modulation of synaptic PPIn turnover by drugs used for the treatment of bipolar disorder is discussed. We propose that the modulation of PPIn levels may act as a central mechanism to coordinate the cascade of synaptic events leading to neurotransmission.