Dopamine D3 receptor modulation of prefrontal cells and circuits

Prefrontal circuits process input from the internal and external world and use these inputs to guide decision-making and subsequent goal-directed behavior. The ability of the prefrontal cortex (PFC) to flexibly guide appropriate behaviors, including updating expectations of reward and punishment, is highly sensitive to neuromodulators such as dopamine. Therefore, elucidating the cellular expression of dopamine receptors on prefrontal projection neurons is critical for understanding how dopamine can act on the prefrontal network, and thereby regulate cognitive and behavioral processes. Dopamine acts in part to regulate the activity of prefrontal layer 5 (L5) principal cells via D1-family (D1/D5) or D2-family (D2/D3/D4) receptors. Recent work indicates that D1- and D2-receptors (D1R/D2R) are expressed in largely separate subclasses of L5 pyramidal cell and that these subclasses have unique electrophysiological features and projection patterns, and are modulated by dopamine via distinct mechanisms. How other dopamine receptor classes are distributed in mPFC is unknown. D3R signaling is critically important for prefrontal executive function, as manipulations perturbing prefrontal D3Rs affect high level cognitive processes such as anxiety and reversal learning. However, the mechanisms by which D3Rs regulate prefrontal cells and circuits remains unknown. By applying a supervised machine learning approach to electrophysiological recordings from dopamine receptor reporter lines, I determine that D3R-expressing (D3+) pyramidal neurons are electrophysiologically distinct from D1R- and D2R-expressing neurons, and therefore likely represent a separate cell subclass. With anatomical tracing techniques, I demonstrate that L5 D3+ neurons are an intratelencephalic cell type. Further experiments reveal that D3R activation within this cell class can regulate calcium channels in the axon initial segment, thereby suppressing action potential burst generation. This provides a mechanism by which modulation via D2-family receptors could directly affect PFC output to other cortical areas