Dynamic Na/K ATPase and neuromodulation of mammalian spinal motor networks

Abstract

Mammalian spinal motor networks are sensitive to neuromodulatory input which can fine tune and adapt motor output. Neuromodulators often act by targeting, either directly or indirectly, neuronal ion channels to change membrane potentials and thus affect the likelihood or rate of action potential generation. The sodium/potassium pump (Na/K ATPase), has recently been linked to a type of post discharge activity termed the ultra-slow after-hyperpolarisation (usAHP). Recent work has also highlighted a potential role for neuromodulators such as dopamine and acetylcholine in modulating this usAHP. The majority of the prior work studying this within spinal cord networks has focussed on the motoneurons, although rhythm generation and control occurs within the diverse and distributed spinal interneuron networks. My thesis aims to investigate the distribution of the usAHP in anatomically mapped spinal interneurons and interrogate the neuromodulatory mechanisms that target the Na/K ATPase pump activity.

Here it is shown, through a combination of electrophysiological and immunohistochemical techniques, that the α3 isoform of the Na/K ATPase primarily linked to the usAHP is broadly expressed across the spinal cord despite the heterogenous display of the usAHP when recording from interneurons across the network. In contrast to previous findings of the effect of modulators enhancing the usAHP in motoneurons, the presented work demonstrates that dopaminergic and muscarinic modulation can reduce post discharge hyperpolarisations in spinal interneurons. Furthermore, during rhythmic output evoked from the isolated spinal cord, both modulators reduce the variability of the network activity in a manner impeded by genetic reduction of α3 pump function. This suggests that neuromodulatory signalling can act via and specifically target the α3 Na/K ATPase to control activity within the spinal locomotor network, to stabilise rhythmic activity. These results indicate that the α3 Na/K ATPase dependent usAHP activity is a powerful mediator of neuromodulatory signalling within spinal locomotor networks.

Date of Award	29 Jun 2026
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Gareth Miles (Supervisor), Matthew Broadhead (Supervisor) & Simon Sharples (Supervisor)