Physiologic role for "inducible" nitric oxide synthase: a new form of astrocytic-neuronal interface.

Nitric oxide (NO) has been long recognized as an atypical neuronal messenger affecting excitatory synaptic transmission, but its cellular source has remained unresolved as the neuronal isoform of NO synthase (nNOS) in many brain regions is expressed only by small subsets of inhibitory neurons. It is generally believed that the glial NO-producing isoform (iNOS) is not expressed in the normal brain, but rather it undergoes a transcription-mediated up-regulation following an immunological challenge. Therefore, the involvement of iNOS in modulating normal neuronal functions has been largely ignored. Here I review evidence to the contrary: I summarize data pointing to the existence of a functioning iNOS in normal undisturbed mammalian brains, and experimental results tracing this expression to astrocytes. Finally, I review recent findings asserting that iNOS-dependent NO modulates synaptic release from presynaptic terminals. Based on these data, I propose that astrocytes express basal levels of iNOS. Flanking synaptic elements, astrocytes are perfectly positioned to release NO and affect synaptic transmission.