Factors mediating powerful voltage attenuation along CA1 pyramidal neuron dendrites

Abstract

We performed simultaneous patch-electrode recordings from the soma and apical dendrite of CA1 pyramidal neurons in hippocampal slices, in order to determine the degree of voltage attenuation along CA1 dendrites. Fifty per cent attenuation of steady-state somatic voltage changes occurred at a distance of 238 microm from the soma in control and 409 microm after blocking the hyperpolarization-activated (H) conductance. The morphology of three neurons was reconstructed and used to generate computer models, which were adjusted to fit the somatic and dendritic voltage responses. These models identify several factors contributing to the voltage attenuation along CA1 dendrites, including high axial cytoplasmic resistivity, low membrane resistivity, and large H conductance. In most cells the resting membrane conductances, including the H conductances, were larger in the dendrites than the soma. Simulations suggest that synaptic potentials attenuate enormously as they propagate from the dendrite to the soma, with greater than 100-fold attenuation for synapses on many small, distal dendrites. A prediction of this powerful EPSP attenuation is that distal synaptic inputs are likely only to be effective in the presence of conductance scaling, dendritic excitability, or both.

Figure 1. Morphology and voltage responses of modelled CA1 pyramidal neurons

A, morphological reconstruction of the three neurons used in this study, with electrode positions in each recording indicated schematically (and providing scale for each neuron). The dendritic recording distances indicated were measured during the experiment. Actual distances in the NEURON models are about 10% longer due to the indirect path between electrodes. B, somatic (large) and dendritic (small) voltage responses to somatic current injections in control ACSF. C, somatic and dendritic voltage responses to somatic current injections in the presence of 5 mm CsCl, which completely blocks the ‘sag.’ Scale bar also applies to B. The current injection protocol is indicated below the leftmost set of traces. The long pulse was −50 pA for 400 ms yielding <3 mv responses in control ACSF (B); in CsCl, the pulse was reduced to −30 pA for cells 1 and 2 (C). The short pulse was 1 ms long, and −1.5 nA in amplitude.

Figure 2. Somatic to dendritic steady-state voltage attenuation

The ratio of the dendritic steady-state voltage response (long current pulse) to the somatic steady-state amplitude is plotted as a function of distance in control (○, n= 34) or with H current blocked (5 mm CsCl, •, n= 16; 50–100 μm ZD7288, ▪, n= 5). Data were fitted with a linear function. The 50% attenuation distance in control was 238 μm and in 5 mm CsCl was 409 μm (extrapolated).

Figure 3. Fits of long and short-current pulse responses using uniform and non-uniform membrane resistance (R_m) models

For non-uniform fits, R_m was allowed to vary as a function of distance, using a sigmoidal function (see Methods). Raw data are indicated in black, and fits are indicated in red. A and B, best fits using uniform R_m (A) and non-uniform R_m (B). C, the R_m gradient, normalized to the somatic R_m, as a function of distance in each of the cells for the apical dendrite. For parameter values of these models see Table 3.

Figure 4. Fits of voltage responses in models containing uniform and non-uniform H conductance

Models of the best fits using non-uniform R_m were used as the underlying passive model. G_h varied as a sigmoidal function of distance (see Methods). Fits were weighted to ensure a match of the steady-state voltage response. Raw data are indicated in black, and fits are indicated in red. A, best fits of the data using models with uniform G_h and non-uniform R_m. The mean square error (MSE) for cell 1 was 0.141 mV, for cell 2, 0.151, and for cell 3, 0.155. B, best fits of the data using models with non-uniform G_h and non-uniform R_m. The MSE for cell 1 was 0.115, for cell 2, 0.147, and for cell 3, 0.079. C, the H conductance gradient, normalized to the somatic G_h value, as a function of distance in each of the cells for the main apical dendrite sections. Somatic G_h for cell 1 was 2.17 pS μm⁻², for cell 2, 16.8 pS μm⁻², and for cell 3, 0.22 pS μm⁻².

Figure 5. Comparison of steady-state attenuation of models having a non-uniform R_m with measured voltage attenuation

A, voltage attenuation with H conductance blocked. Panel at right shows steady-state voltage attenuation for cell 3, with the colour map indicating hyperpolarizing voltage changes of 3 mV (red) to less than 0.3 mV (blue). The filled circles and squares are the same CsCl and ZD7288 attenuation data as in Fig. 2. B, voltage attenuation with H conductance present. Panel at right shows steady-state voltage attenuation for cell 3, with the colour map indicating hyperpolarizing voltage changes of 2 mV (red) to less than 0.2 mV (blue). The ratio of the dendritic to the somatic voltage response (long somatic current injection) is plotted for each section of the primary apical dendrite. Each line corresponds to one model cell. The open circles are the same control attenuation data as in Fig. 2.

Figure 6. Attenuation of EPSPs as they propagate from the dendrite to the soma

A, schematic diagram of the experiments and simulations to measure EPSP attenuation. EPSPs were evoked via a stimulating electrode placed in stratum lacunosum-moleculare and recorded in the dendrite and the soma. For simulations, 40 unitary synaptic inputs in stratum lacunosum-moleculare (as indicated schematically by dots on dendrites) were modelled with a fast conductance increase of 0.1 nS each (0.5 ms rise, 5 ms decay), yielding composite somatic EPSPs of 3.6, 2.0, and 1.8 mV (cells 1, 2, and 3, respectively) at the soma. B, EPSP attenuation (V_soma/V_dendrite) is plotted as a function of distance of the dendritic recording for the six simultaneous somatic/dendritic recordings (○) and for the three models (lines represent attenuation measured from numerous dendritic locations; the cell numbers corresponding to each line are indicated). The inset shows representative EPSPs recorded simultaneously from the soma and dendrite (305 μm). All simulations and recordings were performed with H conductance present (not blocked).

Figure 7. Simulations of EPSP attenuation for various synaptic locations

Non-uniform R_m and G_h models for cell 3 were used in these simulations. The synaptic conductance was 1 nS with a rise time constant of 0.5 ms and a decay time constant of 5 ms. A, the five synapse locations are indicated by the coloured markers (basal site at 135 μm, green; proximal site at 290 μm, blue; side branch site at 322 μm, purple; distal apical at 583 μm, orange; and a second distal apical at 730 μm, yellow) and the somatic and dendritic recording sites are indicated by the electrode cartoons (dendritic recording electrode at 365 μm). B, bar graph showing the amplitude of the somatic EPSP for the five synapses. Results are presented for models with and without H conductance (darker bars and lighter bars, respectively). C, example of simulated EPSPs in response to activation of a distal apical synapse (orange marker in A) and measured at the synapse (orange), the dendritic recording site (black), and at the soma (red). In this example the EPSP attenuates 26-fold between the synapse and the soma.