Nitric Oxide in the Olfactory Bulb: Potential Roles in Physiology and Pathology

The gaseous radical nitric oxide (NO) is generated in the conversion of L-arginine to L-citrulline by nitric oxide synthases (NOS). Being a highly mobile free radical, NO reacts with a wide range of targets. This allows NO to modulate many and various biological functions, from its cardinal role as a potent vasodilator, to neuronal signalling. In mammals, the olfactory bulbs (OB) are the first brain structures to receive and process odour information from the olfactory epithelium (OE), and are among the most prominent nitrergic areas in the rodent brain. Despite this, the acute function of NO in mammalian OBs is unknown. In this thesis, I aim to test the acute electrophysiological effect of NO on the mouse OB in vitro. Hundreds of glomeruli, discrete odour specific neuropils, are the sites of synapses between odour specific axons from the OE and mitral cells (MCs), the principal OB neurons. Glomeruli comprise the circuitry necessary to drive OB output, and are thought to be ideally suited to encapsulate NO. In vitro stimulation of the olfactory nerves entering glomeruli mimics odour input, generating long lasting-depolarisations (LLDs) in all MCs associated with the stimulated glomeruli. In the mouse, MCs are NOS-negative whilst inhibitory interneurons, many of which project within glomeruli and regulate MCs, are the primary source of NO. In this study I tested the effect L-arginine, NO donors, and NOS inhibitors, on stimulated and unstimulated MC activity in OB slices. Increasing NO levels caused reduction in basal MC activity and LLD duration and firing rate, whilst NOS inhibition had the opposite effect. NO was also able to strongly reduce the generation of seizure-like events (SLEs), which sometimes occurred following stimulation. These findings suggest that NO, likely acting within glomeruli, modulates both tonic and stimulated glomerular excitation of MCs. NO, under physiological conditions, may therefore modulate odour sensitivity and discrimination. Conversely, pathological upregulation of NO, well known to cause numerous diseases, may contribute to the myriad of pathologies associated with the OBs, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD)