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

Midbrain dopamine neurons are essential for flexible control of adaptive behaviors. DA neurons that project to different target regions have unique biophysical properties, and it is thought that this diversity reflects functional specialization. This assumption implies the presence of specific genetic determinants with precise impacts on behavior. We tested this general hypothesis by homing in on one particular biophysical mechanism, Kv4 channel inactivation, using a combination of molecular, proteomic, electrophysiological, computational, and behavioral approaches. We demonstrate that KChIP4a, a singular Kv4 {beta}-subunit splice variant, prolongs hyperpolarization-rebound delays selectively in dopamine neurons projecting to the nucleus accumbens core, shifts the integration of inhibitory inputs and, in turn, selectively regulates learning from negative prediction-errors. Our results reveal a highly specialized, gene-to-behavior mechanistic chain that is only operative in a particular dopaminergic subsystem, illuminating how molecularly defined biophysical switches are employed for neuron subtype-specific information processing in the brain. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=70 SRC="FIGDIR/small/344499v3_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@167984borg.highwire.dtl.DTLVardef@3f8fbborg.highwire.dtl.DTLVardef@f5402aorg.highwire.dtl.DTLVardef@147bb3b_HPS_FORMAT_FIGEXP M_FIG C_FIG