A dynamic role for dopamine receptors in the control of mammalian spinal networks

Simon A. Sharples,Patrick J. Whelan,Glen B. Baker,Nicole E. Burma,Ying Zhang,Charlie H. T. Kwok,Joanna Borowska-Fielding,Shane E. A. Eaton,Celine Jean-Xavier,Tuan Trang

doi:10.1038/s41598-020-73230-w

Simon A. Sharples, Patrick J. Whelan + Show 8 more

Open Access

https://doi.org/10.1038/s41598-020-73230-w

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Abstract

Dopamine is well known to regulate movement through the differential control of direct and indirect pathways in the striatum that express D1 and D2 receptors respectively. The spinal cord also expresses all dopamine receptors; however, how the specific receptors regulate spinal network output in mammals is poorly understood. We explore the receptor-specific mechanisms that underlie dopaminergic control of spinal network output of neonatal mice during changes in spinal network excitability. During spontaneous activity, which is a characteristic of developing spinal networks operating in a low excitability state, we found that dopamine is primarily inhibitory. We uncover an excitatory D1-mediated effect of dopamine on motoneurons and network output that also involves co-activation with D2 receptors. Critically, these excitatory actions require higher concentrations of dopamine; however, analysis of dopamine concentrations of neonates indicates that endogenous levels of spinal dopamine are low. Because endogenous levels of spinal dopamine are low, this excitatory dopaminergic pathway is likely physiologically-silent at this stage in development. In contrast, the inhibitory effect of dopamine, at low physiological concentrations is mediated by parallel activation of D2, D3, D4 and α2 receptors which is reproduced when endogenous dopamine levels are increased by blocking dopamine reuptake and metabolism. We provide evidence in support of dedicated spinal network components that are controlled by excitatory D1 and inhibitory D2 receptors that is reminiscent of the classic dopaminergic indirect and direct pathway within the striatum. These results indicate that network state is an important factor that dictates receptor-specific and therefore dose-dependent control of neuromodulators on spinal network output and advances our understanding of how neuromodulators regulate neural networks under dynamically changing excitability.

Highlights

Extracellular neurograms recorded from naïve single lumbar ventral root preparations after applying dopamine in various concentrations
We focused on the modulation of perinatal spontaneous activity patterns to investigate how dopamine modulates spinal network output during a physiologically relevant low excitability state
We show that dopamine has bidirectional concentration-dependent effects on spinal network output in neonatal mice where all dopamine receptor types are expressed[20,31,32] which is consistent with what has been reported in tadpoles at free swimming-stages[12]

Summary

Introduction

Extracellular neurograms recorded from naïve single lumbar ventral root preparations after applying dopamine in various concentrations. We have recently demonstrated that neuromodulation of developing mammalian spinal circuits is statedependent[13] which is consistent with work in invertebrates[14,15] This is important in developing spinal motor networks which produce a wide repertoire of patterned outputs at birth, including locomotor activity, as a consequence of dynamically fluctuating network excitability. We examined how dopamine modulates spinal output at the network and cellular level of neonatal mouse spinal cords in vitro during a low excitability state characterized by spontaneous a ctivity[16,17]. Portions of these data were presented in abstract and preprint form[35,36]

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