Although a number of further studies have now been published exploring possible roles for the NO-cGMP signal transduction system in various models of LTD, there still appears to be confusion regarding the physiological functions of these molecules in the cerebellar cortex. What seems clear is that NO can be produced in granule cells and basket cells, and can stimulate soluble guanylyl cyclase, thereby activating cGMP-dependent protein ldnase in Purkinje cells. However, substrates for this Idnase are still poorly defined, and its (...) role in the modulation of synaptic transmission remains to be determined. The recent development of novel transgenic models and new pharmacological agents with which to dissect this signal transduction system, gives one confidence that our understanding of the cerebellar NO system will quickly advance. With its unique properties as a signaling molecule, it is clear that NO news has been good news for those studying synaptic plasticity in the cerebellum. (shrink)

Interest in the role of nitric oxide (NO) in the nervous system began with the demonstration that glutamate receptor activation in cerebellar slices causes the formation of a diffusible messenger with properties similar to those of the endothelium-derived relaxing factor. It is now clear that this is due to the Ca2+/calmodulin-dependent activation of the enzyme NO synthase, which forms NO and citrulline from the amino acid L-arginine. The cerebellum has very high levels of NO synthase, and although it has low (...) levels of guanylyl cyclase, cerebellar cyclic guanosine monophosphate (cGMP) levels are an order of magnitude higher than in other brain regions. A transcellular metabolic pathway is also present in the cerebellar cortex to recycle citrulline back to arginine. The NO formed binds to and activates soluble guanylyl cyclase to elevate cGMP levels in target cells. Studies employing NADPH-diaphorase, a selective histochemical marker for NO synthase, together with immunohistochemistry, in situ hybridization and biochemical studies have indicated that NO production occurs in granule and basket cells in the cerebellar cortex, whereas cGMP formation appears to occur largely in other cells, including Purkinje cells. Given that a long-term depression of AMPA currents can be seen in isolated Purkinje cells, this anatomical localization suggests that NO cannot play an essential role in the induction of this form of synaptic plasticity. (shrink)