Nitric oxide as a multimodal brain transmitter

One of the simplest molecules in existence, nitric oxide, burst into all areas of biology some 30 years ago when it was established as a major signalling molecule in the cardiovascular, nervous and immune systems. Most regions of the mammalian brain synthesise nitric oxide and it has many diverse roles both during development and in adulthood. Frequently, nitric oxide synthesis is coupled to the activation of NMDA receptors and its physiological effects are mediated by enzyme-linked receptors that generate cGMP. Generally, nitric oxide appears to operate in two main modes: first, in a near synapse-specific manner acting either retrogradely or anterogradely and, second, when multiple nearby sources are active simultaneously, as a volume transmitter enabling signalling to diverse targets irrespective of anatomical connectivity. The rapid diffusibility of nitric oxide and the efficient capture of fleeting, subnanomolar nitric oxide concentrations by its specialised receptors underlie these modes of operation.