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. 2010 Nov 3;30(44):14843-53.
doi: 10.1523/JNEUROSCI.2968-10.2010.

State-dependent firing determines intrinsic dendritic Ca2+ signaling in thalamocortical neurons

Adam C Errington  1 , John J Renger, Victor N Uebele, Vincenzo Crunelli
Affiliations

State-dependent firing determines intrinsic dendritic Ca2+ signaling in thalamocortical neurons

Adam C Errington et al. J Neurosci. .

Abstract

Activity-dependent dendritic Ca(2+) signals play a critical role in multiple forms of nonlinear cellular output and plasticity. In thalamocortical neurons, despite the well established spatial separation of sensory and cortical inputs onto proximal and distal dendrites, respectively, little is known about the spatiotemporal dynamics of intrinsic dendritic Ca(2+) signaling during the different state-dependent firing patterns that are characteristic of these neurons. Here we demonstrate that T-type Ca(2+) channels are expressed throughout the entire dendritic tree of rat thalamocortical neurons and that they mediate regenerative propagation of low threshold spikes, typical of, but not exclusive to, sleep states, resulting in global dendritic Ca(2+) influx. In contrast, actively backpropagating action potentials, typical of wakefulness, result in smaller Ca(2+) influxes that can temporally summate to produce dendritic Ca(2+) accumulations that are linearly related to firing frequency but spatially confined to proximal dendritic regions. Furthermore, dendritic Ca(2+) transients evoked by both action potentials and low-threshold spikes are shaped by Ca(2+) uptake by sarcoplasmic/endoplasmic reticulum Ca(2+) ATPases but do not rely on Ca(2+)-induced Ca(2+) release. Our data demonstrate that thalamocortical neurons are endowed with intrinsic dendritic Ca(2+) signaling properties that are spatially and temporally modified in a behavioral state-dependent manner and suggest that backpropagating action potentials faithfully inform proximal sensory but not distal corticothalamic synapses of neuronal output, whereas corticothalamic synapses only "detect" Ca(2+) signals associated with low-threshold spikes.

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Figures

Figure 1.
Figure 1.
State-dependent firing determines differences in spatial distribution of Δ[Ca2+] in TC neuron dendrites. A, Maximum intensity projection of a typical dLGN neuron illustrating the dendritic sites (also shown in increased magnification, right) where line scans shown in C were performed. Proximal, intermediate, and distal dendritic locations are color coded red, blue, and green, respectively. B, A typical experiment illustrating increase in green fluorescence relative to red fluorescence (G/R) in a TC neuron dendrite resulting from a somatically elicited LTS. C, Dendritic Δ[Ca2+] evoked by LTS (1), single bAP (2), three bAP (200 Hz) burst (3), and 15 bAPs at 30 Hz (4) are shown overlaid onto somatically recorded voltage traces. A single AP transient is shown enlarged for clarity in 2. Black line represents a monoexponential fit to the data. D, Summary of Δ[Ca2+] amplitudes grouped by dendritic location. *p < 0.05 versus proximal Δ[Ca2+]LTS; # p < 0.001 versus proximal Δ[Ca2+]LTS; + p < 0.001 versus Δ[Ca2+]LTS for each dendritic location. n = 6–11 cells. E, Δ[Ca2+] amplitudes, τdecay, and time integrals (Aτ) for LTS-evoked signals as a function of distance from the soma. The plot of Aτ versus distance reveals a more uniform distribution suggesting comparable Ca2+ influx throughout the entire dendritic tree. F, Somatically evoked LTSs produce synchronous Ca2+ transients throughout the entire dendritic tree. Two different pairs of distal dendrites (100–110 μm from the soma) lying in the same focal plane but originating from different stem dendrites (colored tracings constructed from three-dimensional Z series) were imaged separately during evoked LTS activity. In both pairs of dendrites, Δ[Ca2+]LTS occurred simultaneously, and in all four dendrites the amplitude and τdecay of the evoked Ca2+ transients were identical (n = 4 dendrite pairs from 3 neurons).
Figure 2.
Figure 2.
LTSs produce supralinear dendritic Δ[Ca2+]. A, Traces depicting the linear summation of Δ[Ca2+] evoked by one, three, and five bAPs (light gray) compared with Δ[Ca2+]LTS (dark gray) in proximal TC neuron dendrites (20–30 μm). Colored lines represent the modeled linear sum of single bAP Δ[Ca2+] (red) offset for spike timing. B, Plot of amplitude (red) and τdecay (black) for Δ[Ca2+] evoked by bAP (200 Hz) and LTS in the same neurons (n = 11).
Figure 3.
Figure 3.
LTS-evoked dendritic Δ[Ca2+] are essentially AP independent. A, Representative Δ[Ca2+] (top) evoked in a proximal TC neuron dendrite before (gray) and after (black) bath application of TTX (bottom). 1, bAPs (500 ms, 30 Hz) are blocked by TTX along with their corresponding proximal dendritic Δ[Ca2+]. 2, In the absence of Na+ spike bursts, Δ[Ca2+]LTS is slightly reduced at proximal dendritic locations. 3, Distal Δ[Ca2+]LTS is not altered by the addition of TTX. Summary data (n = 9) in inset histograms. B, 1, In current-clamp recording mode, trains of evoked APs produce Δ[Ca2+] that linearly summate and are blocked by TTX. 2, In voltage-clamp recording mode, in the presence of TTX, voltage steps from −50 to +10 mV for 3 ms at a frequency of 50 Hz (to mimic AP firing shown in A) failed to elicit significant Ca2+ accumulation in proximal (20–30 μm) TC neuron dendrites. 3, In contrast, a 700 ms depolarizing step to +10 mV evoked very large Ca2+ influx (sufficient to nearly saturate the Ca2+ indicator), presumably through direct opening of HVA Ca2+ channels.
Figure 4.
Figure 4.
Dendritic Ca2+ accumulation is linearly related to AP firing frequency. A, Typical Δ[Ca2+] evoked in an individual TC neuron proximal dendrite (light gray) by a single bAP and 700 ms spike trains at 10, 30, and 50 Hz (traces truncated for clarity). Overlays (dark gray) show the average [Ca2+]plat pooled from 18 different TC neurons. Decay phases are fitted with monoexponential functions (red lines) to yield τdecay. Dashed lines show baseline and [Ca2+]plat levels. B, Summary of τdecay (black open squares) and ΔG/R (red filled circles) for single bAPs and bAP trains in TC neurons filled with Fluo 5F. τdecay are not significantly (p < 0.05) slowed at firing frequencies up to 50 Hz. C, As in B for Fluo 4FF (500 μm; n = 13). D, Comparison of measured [Ca2+]plat amplitude for individual neurons versus predicted [Ca2+]plat amplitude based on the amplitude and τdecay of the Δ[Ca2+] evoked by a single bAP. Simulations based on τdecay of single Δ[Ca2+]bAP (black symbols) or τdecay for each train evoked [Ca2+]plat (red symbols) showed little deviation from equality (black solid line). Under these conditions, [Ca2+]plat levels are linearly related to firing frequency. E, As in D for Fluo 4FF (n = 8). F, Plot depicting the time constants for Ca2+ accumulation to plateau (τplat) for all frequencies tested. Monoexponential fits to the rising phase of trains evoked Δ[Ca2+] showed little dependency of τplat on firing rate in neurons filled with either Fluo 5F (black) or Fluo 4FF (red). In the presence of lower added buffer, Δ[Ca2+] more rapidly reached steady-state levels. G, [Ca2+]plat is plotted against AP firing frequency for experiments performed using Fluo 5F (Kd of 0.8 μm; black circles) and Fluo 4FF (Kd of 8.1 μm; red squares). Red and black lines represent linear fits to the data for each indicator. The gray line represents a linear fit to the pooled data (excluding 120 Hz, which showed small nonlinearity).
Figure 5.
Figure 5.
Net Ca2+ uptake into ER stores by SERCA during LTS- and bAP-evoked dendritic Δ[Ca2+]. A, Amplitudes of Δ[Ca2+] evoked by a burst of five bAPs (200 Hz) (1) or LTS (2) are not changed by ryanodine (n = 9) or CPA (n = 10), but τdecay is significantly slowed for both in the presence of the SERCA blocker compared with control (n = 11). Traces represent pooled averages of Δ[Ca2+] for each different group of cells. B, 1, Histograms summarize the effects of ryanodine (RYD) and CPA on amplitude and τdecay of Δ[Ca2+]bAP or Δ[Ca2+]5bAPs compared with control neurons (CON) (n = 18, single bAPs; n = 11, 5bAPs) in proximal dendrites. 2, As in 1 for Δ[Ca2+]LTS in proximal and distal dendrites.
Figure 6.
Figure 6.
Global LTS-evoked Δ[Ca2+] are mediated by dendritic T-type Ca2+ channels. A, LTS were blocked by bath application of TTA-P2, and their corresponding dendritic Δ[Ca2+] were abolished. Current injection sufficient to produce somatic depolarization similar in magnitude to LTS could not passively induce increases in dendritic [Ca2+]. B, Action potential trains and their corresponding proximal dendritic [Ca2+]plat were unaffected by TTA-P2. C, Summary histograms of data in A and B. CONT, Control. D, Maximum intensity Z-projection of a dLGN neuron showing placement of a puffer pipette near a distal dendrite for focal application of TTA-P2. Red and blue boxes correspond to the dendritic regions where line scans shown in E were performed. E, 1, Δ[Ca2+] recorded in the dendrite close to the application pipette under control conditions in response to a somatically elicited LTS. 2, During focal application of TTA-P2, the distal Δ[Ca2+] (red) is blocked without changes to the somatic LTS. 3, The Δ[Ca2+] in a contralateral dendrite (blue) is unaffected by the focal application of TTA-P2 at >200 μm away. F, Summary histogram of data in E1 and E2.
Figure 7.
Figure 7.
Distal synaptic inputs evoke LTS and trigger global dendritic Ca2+ influx. A, Traces depicting EPSPs typical of activation of CT afferents by focal synaptic stimulation close to distal dendrites. Varying degrees of synaptic facilitation are observed at different interstimulus intervals. B, 1, Summary plot showing the range of interstimulus intervals that produce marked facilitation of synaptic potentials. 2, Plot describing the degree of paired-pulse facilitation between the first two stimuli of each train. C, Maximum intensity projection of dLGN cell showing proximal (red) and distal (blue) locations imaged on a dendrite contralateral to the stimulated dendrite (white asterisk indicates placement of stimulating electrode). D, 1, An AP evoked by stimulation of local CT afferents produces Ca2+ influx at the proximal dendritic location but not distally. 2, An LTS synaptically triggered from a more hyperpolarized membrane potential evoked Ca2+ influx at both proximal and distal locations. E, Averaged Ca2+ transients (n = 5 cells) in proximal (20–30 μm) and distal (>100 μm) segments of TC neurons resulting from synaptically evoked bAP (1) or LTS (2). Black lines represent monoexponential fits to the data. 3, Summary of the experiments depicted in B. Amplitudes of synaptically evoked Δ[Ca2+]LTS and Δ[Ca2+]bAP are not significantly different from those produced by somatic current injection (n = 5–9; p > 0.05, unpaired t test).
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