Bimodal modulation of short-term motor memory via dynamic sodium pumps in a vertebrate spinal cord

Lamia Hachoumi,Rebecca Rensner,Claire Richmond,Laurence Picton,Hongyan Zhang,Keith T Sillar

doi:10.1016/j.cub.2022.01.012

Lamia Hachoumi, Rebecca Rensner + Show 4 more

Open Access

https://doi.org/10.1016/j.cub.2022.01.012

Copy DOI

Abstract

Dynamic neuronal Na+/K+ pumps normally only respond to intense action potential firing owing to their low affinity for intracellular Na+. Recruitment of these Na+ pumps produces a post-activity ultraslow afterhyperpolarization (usAHP) up to ∼10mV in amplitude and ∼60s in duration, which influences neuronal properties and future network output. In spinal motor networks, the usAHP underlies short-term motor memory (STMM), reducing the intensity and duration of locomotor network output in a manner dependent on the interval between locomotor bouts. In contrast to tonically active Na+ pumps that help set and maintain the resting membrane potential, dynamic Na+ pumps are selectively antagonized by low concentrations of ouabain, which, we show, blocks both the usAHP and STMM. We examined whether dynamic Na+ pumps and STMM can be influenced by neuromodulators, focusing on 5-HT and nitric oxide. Bath-applied 5-HT alone had no significant effect on the usAHP or STMM. However, this is due to the simultaneous activation of two distinct 5-HT receptor subtypes (5-HT7 and 5-HT2a) that have opposing facilitatory and suppressive influences, respectively, on these two features of the locomotor system. Nitric oxide modulation exerts a potent inhibitory effect that can completely block the usAHP and erase STMM. Using selective blockers of 5-HT7 and 5-HT2a receptors and a nitric oxide scavenger, PTIO, we further provide evidence that the two modulators constitute an endogenous control system that determines how the spinal network self-regulates the intensity of locomotor output in light of recent past experience.

Highlights

Neuronal network output is determined by the intrinsic properties of constituent neurons and their synaptic connectivity
Na+ pump inhibition impairs the ultraslow afterhyperpolarization (usAHP) and short-term motor memory To corroborate previous findings that the usAHP of spinal neurons in tadpoles (Figure 1A) is Na+ pump-mediated,[4] the pump inhibitor, ouabain, was applied during patch clamp recordings from spinal central pattern generator (CPG) neurons, where usAHPs were artificially induced by 20 s spike trains.[4] usAHPs (Figure 1B) in control averaged 5.3 ± 1.2 mV in amplitude and 25.48 ± 4.4 s in duration. 0.5 mM ouabain reliably abolished the usAHP (n = 6, p < 0.01; Figures 1B and 1C), an effect not reversible during washout (n = 6, p > 0.05; data not shown)
The ouabain block of the usAHP was not accompanied by any changes in resting membrane potential (RMP) (n = 5, p > 0.05; Figures S1A and S1B), suggesting that dynamic, rather than tonic, Na+ pumps mediate the usAHP, as the latter have a lower affinity for ouabain.[17]

Summary

Introduction

Neuronal network output is determined by the intrinsic properties of constituent neurons and their synaptic connectivity. Over a longer timescale of hours or days, activity-dependent homeostatic regulation of ion channels and transmitter receptors occurs to maintain network output.[1,2] In addition, the activity-dependent recruitment of Na+/K+-ATPases (‘‘Na+ pumps’’) has recently attracted attention as a regulator of network plasticity, in rhythmic motor circuits, that operates over an intermediate timescale of around a minute.[3]. Express Na+ pumps with a lower affinity for Na+ that are recruited only in response to increases in intracellular Na+ resulting from intense neuronal firing. Activation of such ‘‘dynamic’’ Na+ pumps generates an ultraslow afterhyperpolarization (usAHP) lasting up to

Methods

Results

Conclusion