European Journal of Neuroscience, Vol. 27, pp. 2783–2802, 2008 E u r o p e a n J o u r n a l o f N e u r o s c i e n c e doi:10.1111/j.1460-9568.2008.06285.x REVIEW ARTICLE Concepts of neural nitric oxide-mediated transmission John Garthwaite Wolfson Institute for Biomedical Research, University College London, Gower Street, London WCIE 6BT, UK Keywords: cGMP, guanylyl cyclase, retrograde messenger, synaptic plasticity OnlineOpen: This article is available free online at www.blackwell-synergy.com Abstract As a chemical transmitter in the mammalian central nervous system, nitric oxide (NO) is still thought a bit of an oddity, yet this role extends back to the beginnings of the evolution of the nervous system, predating many of the more familiar neurotransmitters. During the 20 years since it became known, evidence has accumulated for NO subserving an increasing number of functions in the mammalian central nervous system, as anticipated from the wide distribution of its synthetic and signal transduction machinery within it. This review attempts to probe beneath those functions and consider the cellular and molecular mechanisms through which NO evokes short- and long-term modiﬁcations in neural performance. With any transmitter, understanding its receptors is vital for decoding the language of communication. The receptor proteins specialised to detect NO are coupled to cGMP formation and provide an astonishing degree of ampliﬁcation of even brief, low amplitude NO signals. Emphasis is given to the diverse ways in which NO receptor activation initiates changes in neuronal excitability and synaptic strength by acting at pre- and ⁄ or postsynaptic locations. Signalling to non-neuronal cells and an unexpected line of communication between endothelial cells and brain cells are also covered. Viewed from a mechanistic perspective, NO conforms to many of the rules governing more conventional neurotransmission, particularly of the metabotropic type, but stands out as being more economical and versatile, attributes that presumably account for its spectacular evolutionary success. Introduction Research into nitric oxide (NO) signalling in the nervous system continues to be fascinating and challenging. It emerged as a signalling molecule in the brain 20 years ago following the search for a missing transmitter that was generated in response to neuronal NMDA receptor activation and caused cGMP generation in other cells (Table 1). Since that time, NO has been implicated in many different neural functions. In peripheral organs, including those of the digestive, respiratory and urogenital tracts, NO performs a neurotransmitter-like role, being released from nitrergic nerves to mediate smooth muscle relaxation (reviewed in Rand & Li, 1995; Toda & Okamura, 2003; Toda & Herman, 2005). In the vertebrate central nervous system (CNS), NO is associated with many different behaviours, including learning and memory formation, feeding, sleeping and male and female reproduc- tive behaviour, as well as in sensory and motor function. Some of these broad roles have been conserved through millions of years of evolution, in some cases dating back to animals with the most primitive nervous systems. In a type of jellyﬁsh, for example, NO evokes the rhythmic swimming pattern associated with feeding, apparently by binding to receptors coupled to cGMP formation, much like the receptors operating in mammals (Moroz et al., 2004). From some of these early cnidarians through to insects and molluscs, a principal function of NO is to regulate olfaction and feeding and their related learning behaviours (see reviews by Davies, 2000; Moroz, 2001; Trimmer et al., 2004; Palumbo, 2005). Following this trend Correspondence: Dr J. Garthwaite, as above. E-mail: john.garthwaite@ucl.ac.uk Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. Received 27 February 2008, revised 21 April 2008, accepted 22 April 2008 through into mammals, common phenotypes of mice deﬁcient in either neuronal NO formation (Huang et al., 1993), or NO receptors (Friebe et al., 2007) or a downstream protein kinase enzyme (Pfeifer et al., 1998), are disturbances in gastrointestinal function. There have been a large number of reviews during the last few years on the roles of NO in many aspects of vertebrate CNS function, including neurogenesis, neuronal differentiation and development (Mize & Lo, 2000; Contestabile & Ciani, 2004; Estrada & Murillo- Carretero, 2005), memory and other behaviours (Golombek et al., 2004; Susswein et al., 2004; Argiolas & Melis, 2005; Del Bel et al., 2005; Nelson et al., 2006), and neuropathology and ⁄ or neuroprotec- tion (Dawson & Dawson, 1998; Contestabile et al., 2003; Keynes & Garthwaite, 2004; Duncan & Heales, 2005; Blokland et al., 2006; Zhang et al., 2006a; Calabrese et al., 2007). The present article attempts to step inside the broader physiological roles of NO and, taking advantage of the substantial recent progress in understanding the cellular and molecular mechanisms it engages, to start to build a picture of how it operates as a signalling molecule. NO synthesis Much is known about the mechanism of NO synthesis from biochemical studies of the puriﬁed NO synthase (NOS) enzymes. They are complex proteins found constitutively in two isoforms, neuronal (nNOS) and endothelial (eNOS). The third, inducible, type (iNOS) is rarely present normally but can be expressed in numerous cell types (prototypically in macrophages, mainly in microglia in the CNS) when subjected to immunological challenge. All three isoforms generate NO from l-arginine but have distinct functional and structural features (reviewed by Alderton et al., 2001; Stuehr et al., ª The Author (2008). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd