A biophysical regulator of inhibitory integration and learning in mesolimbic dopamine neurons

Abstract

Inhibition of midbrain dopamine neurons is thought to underlie the signaling of events that are less rewarding than expected and drive learning based on these negative prediction errors. It has recently been shown that Kv4.3 channels influence the integration of inhibitory inputs in specific subpopulations of dopamine neurons. The functional properties of Kv4.3 channels are themselves strongly determined by the binding of auxiliary β -subunits; among them KChIP4a stands-out for its unique combination of modulatory effects. These include decreasing surface membrane trafficking and slowing inactivation kinetics. Therefore, we hypothesized that KChIP4a expression in dopamine neurons could play a crucial role in behavior, in particular by affecting the computation of negative prediction errors. We developed a mouse line where the alternative exon that codes for the KChIP4a splice variant was selectively deleted in midbrain dopamine neurons. In a reward-based reinforcement learning task, we observed that dopamine neuron-specific KChIP4a deletion selectively accelerated the rate of extinction learning, without impacting the acquisition of conditioned responses. We further found that this effect was due to a faster decrease in the initiation rate of goal-directed behaviors, and not faster increases in action disengagement. Furthermore, computational fitting of the behavioral data with a Rescorla-Wagner model confirmed that the observed phenotype was attributable to a selective increase in the learning rate from negative prediction errors. Finally, KChIP4a deletion did not affect performance in other dopamine-sensitive behavioral tasks that did not involve learning from disappointing events, including an absence of effects on working memory, locomotion and novelty preference. Taken together, our results demonstrate that an exon-and midbrain dopamine neuron-specific deletion of an A-type K + channel β -subunit leads to a selective gain of function in extinction learning. One Sentence Summary:Exon-and midbrain dopamine neuron-specific deletion of the Kv4 channel β -subunit KChIP4a selectively accelerates extinction learning

Subcellular proteomics of dopamine neurons in the mouse brain

“…These results are consistent with the absence of Kv4.3 in the cortical axon proteomic data ( Chuang et al, 2018 ) and ultrastructural studies of Kv4.3 localization in the mouse visual cortex ( Burkhalter et al, 2006 ). Future studies are required to determine the functional role of axonal GIRK2 and Kv4.3 in mDA neurons, but the axonal localization of these K + channels should be considered when interpreting knockout studies ( Costa et al, 2021 ; McCall et al, 2017 ). More broadly, these data suggest that some, but not all, somatodendritic proteins are also in mDA axons.…”