Ca2+-dependent inositol 1,4,5-trisphosphate and nitric oxide signaling in cerebellar neurons

Intracellular Ca(2+) signals are important for the regulation of synaptic functions in the central nervous system. In this review, I summarize findings of our recent studies on upstream and downstream Ca(2+) signaling mechanisms in cerebellar synapses using novel molecular imaging methods. Inositol 1,4,5-trisphosphate (IP(3))-induced Ca(2+) release plays a pivotal role in central synapses. The visualization of IP(3) at fine dendrites of Purkinje cells (PCs) using a fluorescent IP(3) indicator showed that intracellular Ca(2+) concentration has a stimulatory effect on phospholipase C activity, which catalyzes IP(3) production. This indicates that metabotropic and ionotropic glutamate receptors collaborate to generate IP(3) signals. Using a novel nitric oxide (NO) indicator, the spatial distribution of NO signals originating from parallel fiber (PF) terminals was visualized. Our results show that the NO signal decays steeply with distance from the site of production in the cerebellum and is dependent on PF stimulation frequency in a biphasic manner. NO released from PF terminals generated a synapse-specific long-term potentiation of PF-PC synapse when PF was stimulated at certain frequencies. These imaging studies clarified new aspects of the regulatory mechanisms of synaptic functions.