Theta burst stimulation to a synapse evoked localized microdomains of calcium and phosphorylated CaMKII.

(A) Left, The morphology of the model neuron with the highlighted oblique where the synapse was located. All traces and analyses presented in B–G were from this oblique dendrite. Right, The position of the synapse within this oblique is represented in a zoomed version. Also shown is the theta burst stimulus (TBS) protocol where 30 bursts, each made of 5 synaptic stimulation pulses (intra-burst frequency: 100 Hz), were presented at 5 Hz. Across all figures depicting distances from the synapse, to avoid ambiguity, distances towards terminal and trunk are represented as positive and negative numbers, respectively. Inset, Voltage response at the center of the oblique (green) where the synapse is located and simultaneously recorded somatic (black) voltage response to a single burst of the TBS stimulus (100 Hz, five pulses). It may be noted that the local oblique response manifests a dendritic spike (amplitude of voltage response at oblique: 60 mV), which does not propagate to the cell body (amplitude of voltage response at soma: 1 mV) owing to attenuation during its somatodendritic propagation. (B) Voltage responses to TBS recorded at the synaptic location and at different distances, towards the trunk and the terminal, from this location. Trace in red: Voltage response to a single burst of synaptic stimulation, which is highlighted in red on the trace recorded at the synaptic location. (C) Cytosolic calcium [Ca]c traces recorded in response to TBS, at the same locations as that of the voltage response in B. (D–F) Maximum value of cytosolic calcium concentration, (D), minimum value of unbound calmodulin concentration, [CaM]min (E) and maximum value of phosphorylated CaMKII concentration, [pCaMKII]max (F) plotted as functions of distance from the synapse. A double exponential fit (of the form A + B exp(−x/λ1) + C exp(−x/λ2)) to the distance-dependent calcium decay in panel (D) resulted in values for calcium space constants of λ1 = 0.1 μm and λ1 = 2 μm. (G) Kymograph flowchart of the signaling molecules showing the initiation (the calcium trace) and spatiotemporal propagation of microdomains along the signaling cascade. All parameters and channel conductances were assigned to their default values (Fig 1; Tables 1 and 2). Details of parametric values (of active and passive properties in the oblique dendrite shown in Fig 2A) employed for simulations presented in this figure are provided in S1 Table.