Compartment-specific inhibition of bAPs and calcium spikes during BAC firing.

<p>A: Effect of inhibition locus on dendritic coincidence signals, when somatic current injection was paired with dendritic excitation (with a delay Δt of 0 ms) to trigger a calcium spike (as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004768#pcbi.1004768.g001" target="_blank">Fig 1D</a>). As in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004768#pcbi.1004768.g003" target="_blank">Fig 3A</a>, the recording site varies along the rows; the site of inhibition varies along the columns. Inhibitory conductance is indicated by the blue traces (inhibition onset was 1.5 ms after stimulation onset.). a: No inhibition. b: Distal inhibition (460 μm, 50 nS) suppressed the calcium spike (I) and thus distal plasticity, but left signaling in the remaining dendritic tree intact (II and III). c: Proximal inhibition (90 μm, 50 nS) affected signaling in the whole apical dendrite by eliminating the bAP (II), and thus the calcium spike (I), but did not affect the bAP in the basal dendrite (III). d: In the presence of a calcium-spike induced somatic burst, one inhibitory pulse was not sufficient to block the propagation of all bAPs into the basal dendrite (III). e: The train of bAPs in the basal dendrite, and thus basal plasticity, was suppressed by four inhibitory conductance changes at a frequency of 75 Hz on the proximal basal dendrite (100 μm, 70 nS) (III), while apical signaling was unchanged (I and II). B: Inhibition of calcium spikes in the distal apical dendrite. Calcium spikes were triggered by coincident bAPs and distal excitation with a temporal separation (Δt) of 0 ms (as in A). Color-coded is the calcium transient in the apical tuft, normalized to its uninhibited value. While the bAP could be modulated by proximal inhibition within a time window of 1 ms (<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004768#pcbi.1004768.g003" target="_blank">Fig 3B</a>), calcium spikes were rather insensitive to timing, and were abolished by weak distal inhibition. C: Inhibition of calcium spikes in the distal apical dendrite, when the neuron was driven by excitatory synapses distributed along the apical trunk to represent inputs from oblique dendrites (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004768#sec019" target="_blank">Methods</a>). The EPSPs were paired with distal excitation with a temporal separation (Δt) of 0 ms. As in B, the calcium spike could be modulated, less dependent on timing than the bAP.</p

Compartment-specific inhibition of bAPs in the absence of calcium spikes.

<p>A: Effect of inhibition locus on bAPs, elicited by somatic current injection. The recording site varies along the rows; the site of inhibition varies along the columns. Inhibitory conductance is indicated by the blue traces (inhibition onset was 1.5 ms after stimulation onset.). a: No inhibition. b: Distal inhibition (460 μm, 50 nS) affected the distal bAP, but did not have a pronounced effect in the absence of a calcium spike (I), it however left signaling in the remaining dendritic tree intact (II and III). c: Proximal inhibition (90 μm, 50 nS) affected signaling in the whole apical dendrite by eliminating the bAP (II), but did not affect the bAP in the basal dendrite (III). d: The bAP in the basal dendrite, and thus basal plasticity, was suppressed by basal inhibition (100 μm, 50 nS) (III), while apical signaling was unchanged (I and II). B: Effect of inhibition onset timing on bAP and calcium spike modulation. Inhibition was shunting with GABA_A time constants (τ_rise = 0.5 ms, τ_decay = 5 ms). Strength of inhibition varies along each y-axis, onset of inhibition relative to the onset of the somatic step current varies along each x-axis. A: Proximal inhibition on the apical dendrite and its effect on bAPs. The corresponding somatic APs were elicited by somatic step current injection (as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004768#pcbi.1004768.g001" target="_blank">Fig 1C</a>) and peaked around 2.5 ms after stimulation onset. Color-coded is the amplitude of the bAP measured in the oblique dendrite (star indicates recording site). Unless somatic spiking was inhibited (black), either a full-blown bAP (red) or no bAP (light orange) could be observed. C: The neuron was driven by excitatory synapses distributed along the apical trunk to represent inputs from oblique dendrites (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004768#sec019" target="_blank">Methods</a>). Modulation of the bAP was possible in a narrow time window.</p

Circuit model of feedforward inhibition.

<p>A: Topology of the circuit with a multi-compartment pyramidal neuron model and a model of a fast-spiking inhibitory interneuron (IN, targeting pyramidal neuron) receiving excitatory input from a source (EX) at time t₀ and potentially tonic disinhibition (IN, targeting IN). B: Effect of switching the feedforward interneuron on and off (via a second interneuron—marked gray in panel A) measured in the dendrite of the pyramidal neuron (370 μm from the soma), which in turn is driven by apical excitation. Note that the circuit is identical to that in panel A, although the lefthand schematics only zoom in on the interneurons. Upper paradigm: When the feedforward interneuron is switched off (in gray) because of activation of the second interneuron (in black), excitation triggers a spike in the pyramidal cell’s soma which propagates unhindered into the dendrite. Lower paradigm: When the feedforward interneuron is active (in black) due to excitation and because the second interneuron is switched off (in gray), excitation triggers a spike in the pyramidal cell’s soma that does not propagate far into the dendrite due to the inhibition provided by the feedforward interneuron (90 μm from soma, Δt = 2 ms).</p

Analysis of the effect of inhibition on the backpropagating action potential (bAP) in dependence on inhibitory conductance and dendritic location.

<p>The bAP was triggered by threshold somatic current injection (as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004768#pcbi.1004768.g001" target="_blank">Fig 1C</a>). A: Amplitude of the bAP on its path from the soma, along the proximal apical dendrite into the distal oblique dendrite (arrow), normalized to its amplitude at the soma, for different values of inhibition strength (lines in different colors). Inhibition with a double exponential time course (τ_rise = 0.5 ms, τ_decay = 5 ms) was placed on the proximal apical dendrite (90 μm from the soma). Inhibition onset was 2 ms after stimulation onset. The somatic spike peaked around 2.5 ms after stimulation onset. B: Amplitude of the inhibited bAP relative to the non-inhibited bAP as a function of inhibition strength, measured in the distal part of the oblique dendrite (indicated by star in illustration and in A) for different locations of inhibition on the apical trunk (different shades indicate distance to soma in μm, thick line for 90 μm). Inhibition had an all-or-none effect on the bAP.</p

Switching STDP learning rules by inhibition of dendritic signals in a compartment-specific manner.

<p>Results are presented in the same format as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004768#pcbi.1004768.g003" target="_blank">Fig 3A</a>. For each synaptic location, a somatic step current was paired 100 times at 1 Hz with the synaptic activation at different Δt, to simulate a pairing protocol, and to measure the resulting plasticity rule. Inhibition was placed at different locations on the dendritic tree, inhibition onset was 1.5 ms after stimulation onset, rise and decay time constants were 0.5 ms and 5 ms, respectively, the maximum conductance amounted to 50 nS. Synaptic change was normalized to its maximum. A: No inhibition. B: Distal inhibition on the apical dendrite led to a flat STDP window in the distal synapse. C: Proximal inhibition on the apical dendrite caused zero synaptic change in both oblique and distal synapses. D: Proximal inhibition on the basal dendrite abolished STDP in the basal synapse.</p

Response properties of simplified pyramidal neuron model.

<p>The model reproduces qualitative features of pyramidal neuron dendrites found in experiments by [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004768#pcbi.1004768.ref011" target="_blank">11</a>] and [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004768#pcbi.1004768.ref012" target="_blank">12</a>]. The color of the voltage traces match the electrodes in the diagram. Scale bar applies to panels B-E. A: Model neuron morphology with somatic (black) and dendritic (red) recording and stimulation sites. B: EPSP: a distal EPSC (I_stim) resulted in an EPSP in the dendrite with little effect on somatic voltage. C: bAP: threshold somatic current injection (0.3 nA, 2 ms) led to a bAP. D: BAC firing: somatic current injection followed by dendritic stimulation in an interval (Δt) of 5 ms, resulted in a calcium spike, and a burst of two somatic APs. E: Calcium spike: stronger dendritic stimulation alone could elicit a calcium spike. F: Above a critical frequency of somatic spiking, a calcium spike was triggered. The y-axis depicts the cumulative membrane potential across the fixed simulation length of 0.6 sec for different frequencies of somatic stimulation. All values are normalized by the value at 90 Hz stimulation frequency (where a stereotypical calcium spike was elicited). The distal membrane potential changed abruptly once the frequency was high enough to trigger the calcium-dependent dendritic nonlinearity (i.e. the calcium spike).</p

Validation of results in a model cell with anatomically reconstructed morphology.

<p>This model was previously fitted to account for BAC firing by Hay and colleagues [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004768#pcbi.1004768.ref023" target="_blank">23</a>]. Using their original parameters, we replicated the all-or-none modulation of bAPs by proximal inhibition (B), the compartmental modulation of bAPs versus calcium spikes in the morphologically complex dendrite (E-G), and the required time scales for proximal versus distal inhibition (C,E). Ionic conductances in the model by Hay et al. differed from those used in our simplified pyramidal cell model. We found the recovery of the bAP to be independent of the exact ion channel composition of the dendrite, as long as the interplay of sodium and counteracting currents allowed for an active propagation of the sodium spike. A: Morphology of the neuron. Somatic current injection as in [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004768#pcbi.1004768.ref023" target="_blank">23</a>] was used to elicit a bAP. Sites of proximal inhibition (blue) and oblique recording (yellow) are indicated. B: All-or-none modulation of the bAP along the apical dendrite, from the soma into the very distal apical tuft. C: Timing and strength of proximal inhibition (x- and y-axis, respectively) and its effect on the bAP amplitude in the oblique dendrite. Color-code as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004768#pcbi.1004768.g003" target="_blank">Fig 3B/C</a>. D: Somatic current injection paired with dendritic stimulation as in [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004768#pcbi.1004768.ref023" target="_blank">23</a>] was used to trigger BAC firing. Sites of proximal inhibition (blue), distal inhibition and recording (red), and apical tuft (pink) and oblique (yellow) recording are indicated and correspond to colored voltage traces in E to G. E: Distal inhibition inhibited BAC firing, but did not inhibit the bAP in the oblique dendrite. Inhibition of the calcium spike could be achieved for a range of timings (inset, same axes and color code as in B). F: Proximal inhibition inhibited the bAP in the oblique dendrite and BAC firing, if timed appropriately (inset). G: Without inhibition, pairing of bAP and distal input results in BAC firing [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004768#pcbi.1004768.ref023" target="_blank">23</a>].</p