KChIP4a is a Biophysical Amplifier of Inhibition in Atypical Dopamine Neurons and Controls Learning from Negative Prediction Errors.

Dopamine neurons projecting to distinct brain regions have unique biophysical properties, which are thought to reflect functional specialization. One of these defining properties is the duration of hyperpolarization-induced firing pauses, or rebound delays, which are longer in atypical dopamine neurons targeting ventromedial striatal areas like the nucleus accumbens core. Differences in rebound delay are determined by Kv4 channel-mediated A-type currents, but the mechanisms underlying these differences and their functional implications are not well understood. We hypothesized that KChIP4a, a unique Kv4 β-subunit splice variant, determines rebound delay duration in atypical dopamine neurons. To test this, we generated a transgenic mouse line with dopamine neuron-selective removal of KChIP4a. We found that KChIP4a deletion shortened rebound delays in core-projecting atypical dopamine neurons by changing A-type current kinetics, without affecting conventional dopamine neurons. This indicates that KChIP4a acts as a selective biophysical amplifier of hyperpolarizing inhibition in core-projecting dopamine neurons, and computational modeling suggests that this effect is robust across a wide range of in vivo-like conditions for excitation/inhibition balance. Since firing pauses in core-projecting dopamine neurons are thought to drive learning from reward omission, or negative prediction errors, we tested the effect of KChIP4a deletion on different types of behavior in male and female mice. We found that removal of KChIP4a from dopamine neurons selectively accelerated learning from negative prediction errors, without affecting learning from positive prediction errors or other behavioral variables. Together, our results suggest that KChIP4a fine-tunes subthreshold excitability in projection-defined dopamine neuron populations to regulate specific types of learning.