Modulation of corticostriatal plasticity alters the information flow throughout basal ganglia circuits and represents a fundamental mechanism for motor learning, action selection, and reward. Synaptic plasticity in the striatal direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs) is regulated by two distinct networks of GPCR signaling cascades. While it is well-known that dopamine D2 and adenosine A2a receptors bi-directionally regulate iSPN plasticity, it remains unclear how D1 signaling modulation of synaptic plasticity is counteracted by dSPN-specific Gi signaling. Here, we show that striatal dynorphin selectively suppresses long-term potentiation (LTP) through Kappa Opioid Receptor (KOR) signaling in dSPNs. Both KOR antagonism and conditional deletion of dynorphin in dSPNs enhance LTP counterbalancing with different levels of D1 receptor activation. Behaviorally, mice lacking dynorphin in D1 neurons show comparable motor behavior and reward-based learning, but enhanced flexibility during reversal learning. These findings support a model in which D1R and KOR signaling bi-directionally modulate synaptic plasticity and behavior in the direct pathway.
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We thank Dr. Eddy Albarran, Dr. Richard Roth for advice on the paper, Drs. Yu Liu and Xiaobai Ren for technical assistance, and the members of Ding lab for valuable discussions. This work was funded by NINDS/NIH NS091144 (to JBD), NS107315, DK108797, DK046200 (to DK) the GG gift fund (to JBD), the Stanford Bio-X Bowes Graduate Student Fellowship (to RY), and Stanford Neuroscience Institute Interdisciplinary Scholar Awards (to R.R.L.)
The authors declare no competing interests.
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Yang, R., Tuan, R.R.L., Hwang, FJ. et al. Dichotomous regulation of striatal plasticity by dynorphin. Mol Psychiatry 28, 434–447 (2023). https://doi.org/10.1038/s41380-022-01885-0