Role of nitric oxide in cerebellar development and function: focus on granule neurons.

More than 20 years of research have firmly established important roles of the diffusible messenger molecule, nitric oxide (NO), in cerebellar development and function. Granule neurons are main players in every NO-related mechanism involving cerebellar function and dysfunction. Granule neurons are endowed with remarkable amounts of the Ca(2+)-dependent neuronal isoform of nitric oxide synthase and can directly respond to endogenously produced NO or induce responses in neighboring cells taking advantage of the high diffusibility of the molecule. Nitric oxide acts as a negative regulator of granule cell precursor proliferation and promotes survival and differentiation of these neurons. Nitric oxide is neuroprotective towards granule neurons challenged with toxic insults. Nitric oxide is a main regulator of bidirectional plasticity at parallel fiber-Purkinje neuron synapses, inducing long-term depression (LTD) or long-term potentiation (LTP) depending on postsynaptic Ca(2+) levels, thus playing a central role in cerebellar learning related to motor control. Granule neurons cooperate with glial cells, in particular with microglia, in the regulation of NO production through the respective forms of NOS present in the two cellular types. Aim of the present paper is to review the state of the art and the improvement of our understanding of NO functions in cerebellar granule neurons obtained during the last two decades and to outline possible future development of the research.