Extrinsic inputs underscore heterogeneities of ELL pyramidal cell neural activity in awake, behaving weakly electric fish

Heterogeneity in spiking activity is ubiquitous among neurons even within a given cell type. To date, the relative contributions of extrinsic mechanisms (e.g., synaptic bombardment), intrinsic mechanisms (e.g., conductances), and cell morphology toward determining spiking activity remain poorly understood. Here, we addressed this important question using a combination of extracellular in vivo recordings of electrosensory pyramidal cells within weakly electric fish with computational modeling. Specifically, by varying parameters of a conductance-based computational model, we successfully reproduced the highly heterogeneous spiking activities seen experimentally. Model parameters that varied the most were then used to gauge the relative contributions of extrinsic vs. intrinsic mechanisms. Overall, extrinsic synaptic input was predicted to be the main factor accounting for spiking heterogeneity. We tested this prediction experimentally by performing two different manipulations: (1) pharmacologically inactivating feedback from higher brain areas and (2) applying the neuromodulator serotonin. Our model showed that feedback inactivation should reduce spiking heterogeneity, whereas serotonin application should increase it, two predictions that were corroborated experimentally. Importantly, for serotonin application, increased heterogeneity occurred despite a strong reduction in intrinsic membrane conductance, further demonstrating that extrinsic synaptic input is the primary determinant of spiking heterogeneity in vivo. Taken together, our results demonstrate that devising a computational model to capture spiking heterogeneities in vivo and assessing which parameters are responsible can successfully determine the relative contributions of extrinsic inputs, intrinsic properties, and neural morphology.