Abstract
The gaseous free radical, nitric oxide (NO) acts as a ubiquitous neuromodulator, contributing to synaptic plasticity in a complex way that can involve either long term potentiation or depression. It is produced by neuronal nitric oxide synthase (nNOS) which is presynaptically expressed and also located postsynaptically in the membrane and cytoplasm of a subpopulation of each major neuronal type in the ventral cochlear nucleus (VCN). We have used iontophoresis in vivo to study the effect of the NOS inhibitor L‐NAME (L‐NG‐Nitroarginine methyl ester) and the NO donors SIN‐1 (3‐Morpholinosydnonimine hydrochloride) and SNOG (S‐Nitrosoglutathione) on VCN units under urethane anaesthesia. Collectively, both donors produced increases and decreases in driven and spontaneous firing rates of some neurones. Inhibition of endogenous NO production with L‐NAME evoked a consistent increase in driven firing rates in 18% of units without much effect on spontaneous rate. This reduction of gain produced by endogenous NO was mirrored when studying the effect of L‐NAME on NMDA(N‐Methyl‐D‐aspartic acid)‐evoked excitation, with 30% of units showing enhanced NMDA‐evoked excitation during L‐NAME application (reduced NO levels). Approximately 25% of neurones contain nNOS and the NO produced can modulate the firing rate of the main principal cells: medium stellates (choppers), large stellates (onset responses) and bushy cells (primary‐like responses). The main endogenous role of NO seems to be to partly suppress driven firing rates associated with NMDA channel activity but there is scope for it to increase neural gain if there were a pathological increase in its production following hearing loss.
Highlights
It has been suggested that homoeostatic mechanisms maintain firing rates throughout the auditory nervous system, such that, for example, the output from the ventral cochlear nucleus (VCN) to the higher centres of the brain remains close to a long term average even when there are fluctuations in the peripheral input (Noreña, 2011; Schaette & McAlpine, 2011)
Sections were cut at 50 μm and endogenous peroxidase removed by immersing in phosphate buffer (100 mM, pH 7.4) containing 0.3% H2O2 and 10% methanol, followed by phosphate buffer containing 5% normal horse serum (NHS) and 0.5% Triton X‐100
The repolarizing phase of the spike is delayed and this is consistent with an effect on voltage‐dependent potassium channels. Both of these units showed chopper responses, and we studied the inter‐spike interval (ISI) distribution of the first 20 ms of the response during the recovery period compared with the response during the end of the 3‐Morpholinosydnonimine hydrochloride (SIN‐1) application
Summary
It has been suggested that homoeostatic mechanisms maintain firing rates throughout the auditory nervous system, such that, for example, the output from the ventral cochlear nucleus (VCN) to the higher centres of the brain remains close to a long term average even when there are fluctuations in the peripheral input (Noreña, 2011; Schaette & McAlpine, 2011). The afferent inputs from the auditory nerve and the majority of VCN neurones with intrinsic branches are excitatory, while the large stellate onset cells and some small chopping stellates are glycinergic (Doucet, Ross, Gillespie, & Ryugo, 1999; Ngodup & Trussell, 2019) All of these intrinsic neurones can contain nNOS, but within each class there are large variations in the quantity of enzyme present (Coomber et al, 2015). As NO can alter synaptic plasticity, it may have a role in the gain changes that have been suggested as a potential mechanism underlying tinnitus (Noreña, 2011) Such data have led to the postulate that NO levels in the VCN are involved in homoeostatic plasticity (Coomber et al, 2015). The data we present here should represent a valid demonstration of the type of effects that result from nitrergic action during mild stimulation
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