Effects of dendritic Ca2+ spike on the modulation of spike timing with transcranial direct current stimulation in cortical pyramidal neurons.

Transcranial direct current stimulation (tDCS) generates a weak electric field (EF) within the brain, which induces opposite polarization in the soma and distal dendrite of cortical pyramidal neurons. The somatic polarization directly affects the spike timing, and dendritic polarization modulates the synaptically evoked dendritic activities. Ca²⁺ spike, the most dramatic dendritic activity, is crucial for synaptic integration and top-down signal transmission, thereby indirectly influencing the output spikes of pyramidal cells. Nevertheless, the role of dendritic Ca²⁺ spike in the modulation of neural spike timing with tDCS remains largely unclear. In this study, we use morphologically and biophysically realistic models of layer 5 pyramidal cells (L5 PCs) to simulate the dendritic Ca²⁺ spike and somatic Na⁺ spike in response to distal dendritic synaptic inputs under weak EF stimulation. Our results show that weak EFs modulate the spike timing through the modulation of dendritic Ca²⁺ spike and somatic polarization, and such field effects are dependent on synaptic inputs. At weak synaptic inputs, the spike timing is advanced due to the facilitation of dendritic Ca²⁺ spike by field-induced dendritic depolarization. Conversely, it is delayed by field-induced dendritic hyperpolarization. In this context, the Ca²⁺ spike exhibits heightened sensitivity to weak EFs, thereby governing the changes in spike timing. At strong synaptic inputs, somatic polarization dominates the changes in spike timing due to the decreased sensitivity of Ca²⁺ spike to EFs. Consequently, the spike timing is advanced/delayed by field-induced somatic depolarization/hyperpolarization. Moreover, EFs have significant effects on the changes in the timing of somatic spike and Ca²⁺ spike when synaptic current injection coincides with the onset of EFs. Field effects on spike timing follow a cosine dependency on the field polar angle, with maximum effects in the field direction parallel to the somato-dendritic axis. Furthermore, our results are robust to morphological and biological diversity. These findings clarify the modulation of spike timing with weak EFs and highlight the crucial role of dendritic Ca²⁺ spike. These predictions shed light on the neural basis of tDCS and should be considered when understanding the effect of tDCS on population dynamics and cognitive behavior.