Modulation endows neural networks, such as central pattern generators (CPGs) controlling locomotion, with the flexibility required to adjust their output and the behaviours they control to suit varying environmental and organismal demands. Although such modulation is typically thought to originate from neuronal sources, we have recently revealed glial-derived modulation of spinal CPGs by utilising isolated mouse spinal cord preparations in which locomotor-related output can be recorded in vitro. In these preparations, both glial cell activation (via agonists for glial‑specific protease‑activated receptor‑1) and glial cell ablation (using glial toxins), showed that glial cells release ATP in an activity–dependent manner, and that glial-derived ATP is subsequently degraded to adenosine, which in turn modulates the frequency of locomotor-related output via activation of neuronal A1 receptors. Interestingly, this glial-derived modulation is dependent on the co-activation of D1-type dopamine receptors. Whole-cell patch-clamp recordings showed that A1 receptor activation hyperpolarises interneurons and inhibits their synaptic input via presynaptic mechanisms, while A1 receptor activation depolarises motoneurons and has no direct effect on their synaptic inputs. This may allow for adaptation of the locomotor pattern generated by interneuronal networks whilst helping to ensure the maintenance of motor output. Overall, our data indicate that activity-dependent release of purines from glial cells provides negative feedback control of spinal motor networks to regulate, and perhaps stabilise, network output. Given that perturbations in both glial cell function and A1 receptor expression are implicated in neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, our data may contribute to the understanding and eventual treatment of such conditions. FINANCIAL SUPPORT: BBSRC UK, Wellcome Trust, MND Scotland, Motor Neurone Disease Association.
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