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

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.

Contributions of h- and Na+/K+ Pump Currents to the Generation of Episodic and Continuous Rhythmic Activities

“…Episodic activity has been reported in developing spinal circuits for a range of species (Combes et al, 2004;McDearmid and Drapeau, 2006;Gabriel et al, 2011;Wiggin et al, 2012;Gozal et al, 2014;Currie et al, 2016;Sharples and Whelan, 2017;Mahrous and Elbasiouny, 2018;Picton et al, 2018;Kondratskaya et al, 2019). Episodic patterns of rhythmic activity can be generated by the in vitro perinatal mouse spinal cord, and are not specific to dopamine (Sharples and Whelan, 2017;Sharples et al, 2020), but can also be elicited by trace amines (Gozal et al, 2014) or activation of tachykinin receptors (Barbieri and Nistri, 2001;Marchetti and Nistri, 2001), or in juvenile mouse isolated spinal cords (Mahrous and Elbasiouny, 2018). Further, transitions between episodic and continuous patterns can be induced by manipulating neuromodulatory tone or excitability (Sharples and Whelan, 2017).…”

Neural interactions in developing rhythmogenic spinal networks: Insights from computational modeling

“…This awaits additional experimental and computational investigations. A more realistic model of different types of spinal interneurons that includes different ionic channels with experimentally measured characteristics should be developed and investigated (see for example, Sharples et al, 2020), which represents one of the directions of our future investigations.…”

Neural Interactions in Developing Rhythmogenic Spinal Networks: Insights From Computational Modeling

“…This awaits additional experimental and computational investigations. A more realistic model of different types of spinal interneurons that includes different ionic channels with experimentally measured characteristics should be developed and investigated (see for e.g., Sharples et al, 2020 ), which represents one of the directions of our future studies.…”