Intrinsic dendritic integration features of prefrontal layer 5 pyramidal cell subclasses.

Prefrontal cortex (PFC) is an associative center in the brain and integrates various inputs to support cognition. Layer 5 pyramidal cells are themselves associative centers, as their dendrites span all cortical layers and sample multiple input streams. Backpropagating action potentials (bAPs) are an important mechanism for integrating synaptic inputs arriving at distinct dendritic locations. bAPs originating in the axon initial segment can depolarize the apical dendrite, activate voltage-gated currents that underlie dendritic processing and synaptic plasticity, and influence the integration of synaptic inputs arriving onto apical dendrites. How effectively bAPs depolarize apical dendrites depends on cell type, dendritic morphology, and the dendrite's passive and active properties. Here, we found that in a unique subclass of PFC layer 5 pyramidal cell defined by D3 dopamine receptor (D3R) expression, dendritic calcium responses to bAP stimuli were far greater for a burst of APs than expected from a linear sum of single AP-evoked events in mice of either sex. D3R-expressing neurons electrophysiologically resemble intratelencephalic, D1R-expressing pyramidal neurons but morphologically resemble pyramidal tract, D2R-expressing pyramidal neurons. In both D1R- and D2R-expressing cells, burst-evoked dendritic calcium events largely reflected a linear sum of individual AP responses. In D1R neurons, this was partially due to large conductance calcium-activated potassium (BK) channels, while in D2R neurons, both BK and hyperpolarization-activated cyclic nucleotide-gated channels contributed. These data demonstrate that the intrinsic dendritic excitability of PFC layer 5 pyramidal cells widely differs and suggest that nonlinear dendritic excitability in D3R-expressing neurons uniquely positions these cells within PFC circuits.Significance Statement Layer 5 pyramidal cells associate inputs from diverse information streams to shape behavior. Backpropagating action potentials (bAPs) enable the integration of synaptic inputs that arrive coincidentally on the basal and apical dendrites, but the extent to which bAPs depolarize the apical dendrites can vary across cell types and dendritic morphologies. In prefrontal cortex, layer 5 pyramidal cells can be distinguished based on expression of the D1, D2, or D3 dopamine receptor expression. Here, we examined intrinsic dendritic excitability across D1R, D2R and D3R-expressing neurons and found that bAP-associated dendritic calcium transients vary considerably across these three intermingled neuronal subtypes, suggesting that these pyramidal cell classes have unique roles in prefrontal cortex processing.