Long-Term Neuromodulatory Effects on the Ionic Current Parameter Space of Oscillatory Neurons

Neurons are constantly subject to short-term neuromodulatory effects through the regulation of various proteins, including ion channels. However, the long-term influences of neuromodulators remain poorly understood. Multiple ionic currents work in concert to generate oscillatory neuronal activity, and long-term neuromodulatory effects on them likely differ from short-term effects. Here we examined the long-term effects of the neuromodulatory environment on the ionic conductances that generate the rhythmic activity of a well-known neuronal network, the crustacean pyloric network. We measured most of the known voltage-dependent and synaptic currents expressed by two identified neurons in their normal neuromodulatory environment and after prolonged removal of neuromodulators. To understand the global conductance makeup of these cells, we defined the conductance parameter space of each cell as the multidimensional volume occupied by its conductances in a population of identical neurons. We then examined the changes in this volume after independently modifying the neuromodulator environment and activity of these neurons. Both neuromodulation and activity appear to constrain the conductance parameter space in pyloric neurons, suggesting a general phenomenon. Interestingly, while neuromodulators appear to exert a similar regulatory effect on both cells, activity seems to do so in a cell-type-specific manner. Our results suggest a mechanism that explains why the same manipulation of the neuromodulatory input does not produce the same change in network activity across animals: the degeneracy of the pacemaker mechanism. Significance How does a rhythm-generating neuronal network recover its rhythm after its disruption? Neuromodulators control neuronal activity, especially rhythmic activity, which is vital to animals. Thus, neuronal network robustness and the ability to recover from major perturbations are of crucial importance. We tested the hypothesis that neuromodulators constrain the entire neuronal ionic conductance parameter space in a well-characterized network. Our results confirm that neuromodulators and activity regulate the global neuronal conductance landscape. Our results suggest a mechanism that explains why the same manipulation of the neuromodulatory environment produces distinct effects on network activity across individuals: the degeneracy of the pacemaker mechanism. These results support the need to consider individualized approaches to understand functional mechanisms and to develop therapies for pathological conditions.