Abstract
Nitric oxide (NO) is of fundamental importance in regulating immune, cardiovascular, reproductive, neuromuscular, and nervous system function. It is rapidly synthesized and cannot be confined, it is highly reactive, so its lifetime is measured in seconds. These distinctive properties (contrasting with classical neurotransmitters and neuromodulators) give rise to the concept of NO as a “volume transmitter,” where it is generated from an active source, diffuses to interact with proteins and receptors within a sphere of influence or volume, but limited in distance and time by its short half-life. In the auditory system, the neuronal NO-synthetizing enzyme, nNOS, is highly expressed and tightly coupled to postsynaptic calcium influx at excitatory synapses. This provides a powerful activity-dependent control of postsynaptic intrinsic excitability via cGMP generation, protein kinase G activation and modulation of voltage-gated conductances. NO may also regulate vesicle mobility via retrograde signaling. This Mini Review focuses on the auditory system, but highlights general mechanisms by which NO mediates neuronal intrinsic plasticity and synaptic transmission. The dependence of NO generation on synaptic and sound-evoked activity has important local modulatory actions and NO serves as a “volume transmitter” in the auditory brainstem. It also has potentially destructive consequences during intense activity or on spill-over from other NO sources during pathological conditions, when aberrant signaling may interfere with the precisely timed and tonotopically organized auditory system.
Highlights
Nitric oxide (NO) is a small molecule, highly mobile, highly reactive and soluble in water and lipid membranes, so that once synthesized it cannot be contained
It is often difficult to identify the source of NO signaling for a specific physiological or behavioral output, and difficult to separate physiological roles from pathological consequences, with the potential for spill-over from one synthase into the signaling system of another, e.g., iNOS to neuronal nitric oxide synthase (nNOS) (Hopper and Garthwaite, 2006)
Microglia are present in the auditory brainstem, where they are involved in developmental pruning of the calyx of Held synapse (Milinkeviciute et al, 2019) and in regulating inflammation
Summary
Nitric oxide (NO) is a small molecule, highly mobile, highly reactive and soluble in water and lipid membranes, so that once synthesized it cannot be contained. The generation of cGMP, NO-induced intrinsic plasticity, synaptic plasticity and changes in in vivo firing rates have been clearly demonstrated in the auditory brainstem: cochlear nucleus: (Cao et al, 2019; Hockley et al, 2019, 2020), Superior Olivary Complex: (Steinert et al, 2008, 2011; Tozer et al, 2012; Yassin et al, 2014; Kopp-Scheinpflug et al, 2015), and Inferior Colliculus: (Olthof et al, 2019) and in an animal model of tinnitus (Coomber et al, 2014, 2015).
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