Metamodulation of a Spinal Locomotor Network by Nitric Oxide

Abstract

Flexibility in the output of spinal networks can be accomplished by the actions of neuromodulators; however, little is known about how the process of neuromodulation itself may be modulated. Here we investigate the potential "meta"-modulatory hierarchy between nitric oxide (NO) and noradrenaline (NA) in Xenopus laevis tadpoles. NO and NA have similar effects on fictive swimming; both potentiate glycinergic inhibition to slow swimming frequency and GABAergic inhibition to reduce episode durations. In addition, both modulators have direct effects on the membrane properties of motor neurons. Here we report that antagonism of noradrenergic pathways with phentolamine dramatically influences the effect of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) on swimming frequency, but not its effect on episode durations. In contrast, scavenging extracellular NO with 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) does not influence any of the effects of NA on fictive swimming. These data place NO above NA in the metamodulatory hierarchy, strongly suggesting that NO works via a noradrenergic pathway to control glycine release but directly promotes GABA release. We confirmed this possibility using intracellular recordings from motor neurons. In support of a natural role for NO in the Xenopus locomotor network, PTIO not only antagonized all of the effects of SNAP on swimming but also, when applied on its own, modulated both swimming frequency and episode durations in addition to the underlying glycinergic and GABAergic pathways. Collectively, our results illustrate that NO and NA have parallel effects on motor neuron membrane properties and GABAergic inhibition, but that NO serially metamodulates glycinergic inhibition via NA.

A role for nitric oxide in the control of breathing in zebrafish (Danio rerio)

“…Lastly, NO has been described as a 'meta-modulator' of neural activity (McLean and Sillar, 2004), and in frogs the role of NO changes through development. NO inhibits swimming via indirect glycinergic and direct GABAergic inhibition Sillar, 2002, 2004); however, in frogs, endogenous production of NO might not be fully developed at earlier stages of development (McLean and Sillar, 2004).…”

“…NO inhibits swimming via indirect glycinergic and direct GABAergic inhibition Sillar, 2002, 2004); however, in frogs, endogenous production of NO might not be fully developed at earlier stages of development (McLean and Sillar, 2004). Therefore, it is possible that modulation of NO in zebrafish larvae is also not fully developed at 4 dpf owing to a lack of inhibitory targets.…”

Nitric Oxide Potentiation of Locomotor Activity in the Spinal Cord of the Lamprey

“…NO promotes this immobility by selectively enhancing GABAergic descending inhibition from midhindbrain reticulospinal interneurons and by enhancing glycinergic inhibition during swimming (McLean and Sillar, 2002). This latter effect involves metamodulation of the effects of noradrenaline (McLean and Sillar, 2004). Therefore, compared with the lamprey, the predominant effects of NO are (1) inhibitory and (2) mediated in the brainstem.…”

A newly identified extrinsic input triggers a distinct gastric mill rhythmviaactivation of modulatory projection neurons

“…Further flexibility in the output of these motor circuits is afforded by modulatory actions at the level of the projection neurons that drive circuit activity (Di Prisco et al, 2000;Blitz et al, 2004;McLean and Sillar, 2004;Brocard et al, 2005;Smetana et al, 2007). However, the extrinsic inputs that provide these modulatory influences on projection neurons are not well-documented in most systems.…”