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Nonlinear synaptic integration in dendrites is a fundamental aspect of neural computation. One such key mechanism is the Ca 2+ spike at the apical tuft of pyramidal neurons. Characterized by a plateau potential sustained for tens of milliseconds, the Ca 2+ spike amplifies excitatory input, facilitates somatic action potentials (APs), and promotes synaptic plasticity. Despite its essential role, the mechanisms regulating it are largely unknown. Using a compartmental model of a layer 5 pyramidal cell (L5PC), we explored the plateau and termination phases of the Ca 2+ spike under input current perturbations, long-step current-injections, and variations in the dendritic high-voltage-activated Ca 2+ conductance (that occur during cholinergic modulation). We found that, surprisingly, timed excitatory input can shorten the Ca 2+ spike duration while inhibitory input can either elongate or terminate it. A significant elongation also occurs when the high-voltage-activated Ca 2+ channels (Ca HVA ) conductance is increased. To mechanistically understand these phenomena, we analyzed the currents involved in the spike. The plateau and termination phases are almost exclusively controlled by the Ca HVA inward current and the I m outward K + current. We reduced the full model to a single-compartment model that faithfully preserved the responses of the Ca 2+ spike to interventions and consisted of two dynamic variables: the membrane potential and the K + -channel activation level. A phase-plane analysis of the reduced model provides testable predictions for modulating the Ca 2+ spike and reveals various dynamical regimes that explain the robust nature of the spike. Regulating the duration of the Ca 2+ spike significantly impacts the cell synaptic-plasticity window and, as we show, its input-output relationship. SIGNIFICANCE STATEMENT Pyramidal neurons are the cortex's principal projection neurons. In their apical tuft, dendritic Ca 2+ spikes significantly impact information processing, synaptic plasticity, and the cell's input-output relationship. Therefore, it is essential to understand the mechanisms regulating them. Using a compartmental model of a layer 5 pyramidal cell (L5PC), we explored the Ca 2+ spike responses to synaptic perturbations and cholinergic modulation. We showed a counterintuitive phenomenon: early excitatory input shortens the spike, whereas weak inhibition elongates it. Also, we demonstrated that acetylcholine (ACh) extends the spike. Through a reduced model containing only the membrane potential and the K + -channel activation level, we explained these phenomena using a phase-plane analysis. Our work provides new information about the robustness of the Ca 2+ spike and its controlling mechanisms.

Synaptic Input and ACh Modulation Regulate Dendritic Ca2+Spike Duration in Pyramidal Neurons, Directly Affecting Their Somatic Output

Synaptic Input and ACh Modulation Regulate Dendritic Ca²⁺Spike Duration in Pyramidal Neurons, Directly Affecting Their Somatic Output