On the initiation and propagation of dendritic spikes in CA1 pyramidal neurons - PubMed (original) (raw)

On the initiation and propagation of dendritic spikes in CA1 pyramidal neurons

Sonia Gasparini et al. J Neurosci. 2004.

Abstract

Under certain conditions, regenerative voltage spikes can be initiated locally in the dendrites of CA1 pyramidal neurons. These are interesting events that could potentially provide neurons with additional computational abilities. Using whole-cell dendritic recordings from the distal apical trunk and proximal tuft regions and realistic computer modeling, we have determined that highly synchronized and moderately clustered inputs are required for dendritic spike initiation: approximately 50 synaptic inputs spread over 100 mum of the apical trunk/tuft need to be activated within 3 msec. Dendritic spikes are characterized by a more depolarized voltage threshold than at the soma [-48 +/- 1 mV (n = 30) vs -56 +/- 1 mV (n = 7), respectively] and are mainly generated and shaped by dendritic Na+ and K+ currents. The relative contribution of AMPA and NMDA currents is also important in determining the actual spatiotemporal requirements for dendritic spike initiation. Once initiated, dendritic spikes can easily reach the soma, but their propagation is only moderately strong, so that it can be modulated by physiologically relevant factors such as changes in the V(m) and the ionic composition of the extracellular solution. With effective spike propagation, an extremely short-latency neuronal output is produced for greatly reduced input levels. Therefore, dendritic spikes function as efficient detectors of specific input patterns, ensuring that the neuronal response to high levels of input synchrony is a precisely timed action potential output.

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Figures

Figure 1.

Figure 1.

High-intensity, EPSC-shaped currents evoke dendritic spikes. A, Experimental configuration. EPSC-shaped currents of increasing intensity were injected into distal (>250 μm) dendrites of pyramidal CA1 neurons through a whole-cell electrode, and the voltage was recorded with another electrode placed 20 μm distant. B, The voltage responses were typically linear for lower current intensities, whereas the generation of a dendritic spike resulted in a nonlinear EPSP peak amplitude versus current (I-V) plot for higher current injections (C). D, The voltage threshold for dendritic spikes was defined as the voltage at which the second peak of the second temporal derivative reaches 20% of its maximal value. E, The voltage threshold for dendritic spikes, calculated at 294 ± 6 μm, was higher (-48 ± 1 mV; n = 30) than for somatic spikes (-56 ± 1 mV; n = 7). F, The voltage threshold for dendritic spikes was inversely correlated to the rate of membrane depolarization (dV/dt) preceding the spike.

Figure 2.

Figure 2.

Active currents involved in generating and shaping dendritic spikes. A, TTX (0.5 μ

m

) blocked the generation of local dendritic spikes and eliminated the supralinearity in the I-V plot, which actually became sublinear for high current intensities. B, 4-AP (5 m

m

) lowered the current threshold for the generation of dendritic spikes and increased their amplitude. 4-AP also increased the amplitude of dendritic spikes (from 67 ± 1 to 93 ± 3 mV; p < 0.0001; n = 8) and decreased their voltage threshold (from -45 ± 1 to -52 ± 1 mV; p < 0.0001; n = 8). For higher current intensities, back-propagating spikes (asterisk) could be recorded. C, Ba2+ (20 μ

m

) increased the amplitude of dendritic spikes and decreased the current threshold for their generation, but the voltage threshold was not affected (from -48 ± 1 mV in control conditions to -48 ± 1 mV in the presence of Ba2+; p > 0.2; n = 8).

Figure 3.

Figure 3.

Temporal requirements for dendritic spike generation. A, For every neuron, the current required to initiate a dendritic spike was measured for a completely synchronous input (inset calibration: 10 mV, 5 msec). This level was divided in five unitary inputs that were then injected with increasing intervals from 0.1 to 5 msec. For example, in this CA1 neuron, the threshold current was 4.0 nA, and it was divided into five inputs of 0.8 nA each. With the asynchronous inputs, a dendritic spike could be evoked only for intervals ≤0.5 msec, because it appears also in the average plot. B, Dendritic spikes were evoked only for intervals ≤0.2 msec in dynamic-clamp configuration, when conductances with the characteristics of only AMPA receptors were generated. C, When AMPA and NMDA conductances were coinjected (AMPA/NMDA, 2:1), the time window for dendritic spike generation broadened to 0.5 msec. In the three average plots, the peak amplitudes were normalized to the amplitude of the elementary input for each experiment [9.3 ± 0.3 mV (n = 7) in A, 8.5 ± 0.6 mV (n = 12) in B, and 8.2 ± 1.2 (n = 8) in _C_].

Figure 4.

Figure 4.

Spatial requirements for dendritic spike generation. A, Experimental configuration. Two dendritic electrodes placed at different distances (85 μm in this case) were used to inject EPSC-shaped currents and measure the current threshold to generate a dendritic spike when the current was injected through either one or both of the electrodes together. In this neuron, the current threshold was 4.0 nA for one electrode, whereas 3.0 nA had to be injected simultaneously in both of the electrodes to initiate a dendritic action potential (the total current threshold in this case was 6.0 nA). The relative current threshold was thus 1.5 times higher than in the case of the injection through one single electrode. B, Plot of the current threshold required for a dendritic spike when injected through two electrodes (normalized to the “single” current threshold) as a function of the distance between the two electrodes.

Figure 5.

Figure 5.

Effects of realistic spatial and temporal patterns on dendritic spike initiation. A, A multicompartment model qualitatively reproduces the experimental findings on the temporal patterns required for dendritic spike initiation in the case of five inputs (compare Fig. 3). The same temporal patterns were used to model current-clamp (left; unitary peak current, 0.23 nA) and dynamic-clamp (middle; unitary peak conductance, 5.2 nS) conditions for the case of AMPA-only or AMPA plus NMDA (right; unitary peak conductances for AMPA and NMDA of 4 and 1 nS, respectively) conductances. B, I-V plots of the EPSP spike amplitude, normalized to the amplitude of the elementary input, as a function of the number of inputs for current injections (left), AMPA-only conductances (middle), and AMPA plus NMDA conductances (right). C, Contour plots of the spike probability (calculated from 30 simulations) as a function of the spatial and temporal distribution for 53 AMPA-only (left) and for AMPA plus NMDA (ratio, 4:1; right) synapses (the minimal number needed to reach threshold in the case of AMPA-only conductances activated synchronously in the same location). D, Imposition of high-conductance conditions (see Materials and Methods) does not affect spike probability for input patterns near threshold [53 synapses given at the same location within 3.7 msec (left) or over 100 μm distance within 3.5 msec (right)]. In all cases (black, control; red, high conductance), dendritic spikes are initiated 2 of 10 times. E, Plot of the maximal time over which the synaptic inputs can be distributed as a function of the number of activated inputs over a spatial distribution of 50 μm (left) or 100 μm (right).

Figure 6.

Figure 6.

Dendritic spike propagation depends on the _V_m and interactions with transient depolarizations. A, A dendritic spike was evoked by injecting EPSC-shaped currents in one electrode, and the amplitude of the propagated signal was measured at different distances (100 μm in this case). As seen in the individual traces, the extent of propagation was highly dependent on the _V_m, with depolarization to approximately -60 mV removing almost all the decrement. B, Pooled data of the propagated spike amplitude as a function of the distance between the two electrodes. Near rest (-65 ± 1 mV; green circles), the amplitude was ∼40 mV at 150 μm from the initiation site, and it was decreased by hyperpolarization (red circles) and increased by depolarization (blue circles). C, A subthreshold EPSP-like depolarization was evoked with a proximal dendritic electrode (∼175 μm from the soma), whereas a dendritic spike was initiated at a more distal recording site by a second electrode (∼275 μm from the soma) with different time intervals between the current injections (0-30 msec). It can be seen from the individual traces and from the pooled data (D; distance between pipettes ranged from 80 to 140 μm; n = 4) that the transient depolarization was highly effective in boosting the propagating spike when the two events were closely timed. The amount of spike amplitude boosting followed the temporal profile of the subthreshold transient depolarization. This indicates that propagating dendritic spikes and other transient dendritic depolarizations, similar to large EPSPs or other failed dendritic spikes, could interact in a complicated manner.

Figure 7.

Figure 7.

Changes in extracellular K+ and Ca2+ decrease initiation and propagation of dendritic spikes. A, Images of bis-fura-2-filled dendrites from two different CA1 pyramidal neurons in solutions containing 3.0 m

m

[KCl] and 1.3 m

m

[CaCl2] (physiological solution; left) or 2.5 m

m

[KCl] and 2.0 m

m

[CaCl2] (low-K+ solution; right). The tip of the electrode was approximately in the area delimited by the red box in A [at a distance of 320 μm (left) and 280 μm (right) from the soma]. B, Voltage responses to a 50 Hz train of EPSC-shaped currents. The stimulation intensities were 3 nA (left) and 2.5 nA (right). C, Optical recordings showing the Δ_F_/F associated with the dendritic spikes shown in B (average of 5 traces). D, Average data of the normalized Ca2+ influx associated with local dendritic spikes as a function of the distance from the recording electrode in the two different solutions (*p < 0.01). Although in the physiological solution the Ca2+ influx decreased only by 27 ± 4% (n = 11) at 100 μm, in the low-K+ solution, the decrease was 64 ± 1% (n = 7). E, Raising [Ca2+]o from 1.3 to 2.0 m

m

and decreasing [K+]o from 3.0 to 2.5 m

m

depressed dendritic excitability. The membrane potential hyperpolarized (from -67 ± 1 to 69 ± 1 mV; p < 0.01; n = 16), the input resistance at steady state decreased (from 39 ± 3 to 34 ± 2 MΩ; p < 0.01; n = 16), and the temporal summation, measured as the ratio between the fifth and the first EPSP (for a 1.5 nA injection at 50 Hz), decreased (from 12 ± 3 to 7 ± 3%; p < 0.02; n = 8). Dendritic spike initiation was also reduced by the shift from the new solution to the old one because more current was required to evoke them. Also, the voltage threshold for dendritic spike initiation was more depolarized (from -44 ± 1 to 49 ± 1 mV; p < 0.002; n = 7). F, The mean current-voltage relationship for the first and the second iEPSPs is shifted to the right in the 2.0 m

m

Ca and 2.5 m

m

K solution. The current values are normalized to the current threshold necessary to evoke a dendritic spike in the physiological solution.

Figure 8.

Figure 8.

The somatic impact of dendritically initiated spikes. A, Experimental configuration. A dendritic electrode (blue traces) located 285 μm from the soma was used to inject current and record voltage, while the response at the soma was recorded with a second electrode. B, Effect of the _V_m on signal propagation to the soma. Left, The injection of relatively small amounts of EPSC-shaped current (2 nA) does not evoke a dendritic spike but travels to the soma, where it provides enough slow depolarization to initiate a somatic action potential at this more depolarized _V_m (-62 mV; green trace from the soma). The spike recorded in the dendritic trace is back-propagating. Middle, Larger current injections (4 nA) lead to the initiation of a dendritic spike and the subsequent generation of a short-latency somatic action potential at the normal _V_m (-67 mV; black trace from the soma). Right, At hyperpolarized potentials (-72 mV; red trace from the soma), a dendritic spike is initiated by the large current injection (4 nA), but it is unable to propagate to the soma effectively enough to evoke an action potential output. C, Superimposition of the somatic recordings from B. Notice the apparently lower threshold for the spike evoked at -67 mV and the fast iEPSP rise time with the _V_m at -72 mV. D, I-V plot of the depolarization recorded at the soma after dendritic current injections at the normal _V_m (black triangles; n = 5), at hyperpolarized potentials (red circles; n = 7), and in the presence of TTX (blue squares; n = 4). The gray line shows the action potential threshold for slow somatic depolarizations without dendritic spikes with respect to the average _V_m (-65 ± 1 mV; n = 5). E, First derivative (dV/dt) of the traces in C. The enlargement (bottom) shows the initial ramp component that is only present when a dendritic spike is evoked (black and red traces). The plot shows that this initial ramp can be further broken into two separate components: one that is larger and present only when propagation is strong enough to evoke action potential output (labeled second; black trace; shaded region), and another that is present regardless of a somatic spike (labeled first; black and red traces). F, Plot of the most hyperpolarized _V_m at which a dendritic spike could still evoke a short-latency somatic output (<2 msec). Short-latency action potential output could not be evoked in two neurons when dendritic current injection initiated a spike in the apical tuft region. In these cells, action potential threshold at the soma was reached at the peak of the iEPSP (∼7 msec) and was therefore considered to be the result of summation (summ only) and not the direct result of the strong propagation of the dendritic spike. G, The amplitude of the first component of the initial dV/dt ramp depends on the distance of the injection site from the soma and other factors influencing spike propagation. The second component of the initial dV/dt ramp exhibited a similar location dependence (data not shown).

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