Locomotion activates PKA through dopamine and adenosine in striatal neurons

Lei Ma, Julian Day-Cooney, Omar Jáidar Benavides, Michael A. Muniak, Maozhen Qin, Jun B. Ding, Tianyi Mao and Haining Zhong ()
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Lei Ma: Oregon Health and Science University
Julian Day-Cooney: Oregon Health and Science University
Omar Jáidar Benavides: Stanford University School of Medicine
Michael A. Muniak: Oregon Health and Science University
Maozhen Qin: Oregon Health and Science University
Jun B. Ding: Stanford University School of Medicine
Tianyi Mao: Oregon Health and Science University
Haining Zhong: Oregon Health and Science University

Nature, 2022, vol. 611, issue 7937, 762-768

Abstract: Abstract The canonical model of striatal function predicts that animal locomotion is associated with the opposing regulation of protein kinase A (PKA) in direct and indirect pathway striatal spiny projection neurons (SPNs) by dopamine1–7. However, the precise dynamics of PKA in dorsolateral SPNs during locomotion remain to be determined. It is also unclear whether other neuromodulators are involved. Here we show that PKA activity in both types of SPNs is essential for normal locomotion. Using two-photon fluorescence lifetime imaging8–10 of a PKA sensor10 through gradient index lenses, we measured PKA activity within individual SPNs of the mouse dorsolateral striatum during locomotion. Consistent with the canonical view, dopamine activated PKA activity in direct pathway SPNs during locomotion through the dopamine D1 receptor. However, indirect pathway SPNs exhibited a greater increase in PKA activity, which was largely abolished through the blockade of adenosine A2A receptors. In agreement with these results, fibre photometry measurements of an adenosine sensor11 revealed an acute increase in extracellular adenosine during locomotion. Functionally, antagonism of dopamine or adenosine receptors resulted in distinct changes in SPN PKA activity, neuronal activity and locomotion. Together, our results suggest that acute adenosine accumulation interplays with dopamine release to orchestrate PKA activity in SPNs and proper striatal function during animal locomotion.

Date: 2022
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DOI: 10.1038/s41586-022-05407-4

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