A model of a CA3 hippocampal pyramidal neuron incorporating voltage-clamp data on intrinsic conductances

Abstract

We have developed a 19-compartment cable model of a guinea pig CA3 pyramidal neuron. Each compartment is allowed to contain six active ionic conductances: g(Na), g(Ca), g(K(DR)) (where DR stands for delayed rectifier), g(K(A)), g(K(AHP)), and g(K(C)). The conductance g(Ca) is of the high-voltage activated type. The model kinetics for the first five of these conductances incorporate voltage-clamp data obtained from isolated hippocampal pyramidal neurons. The kinetics of g(K(C)) are based on data from bullfrog sympathetic neurons. The time constant for decay of submembrane calcium derives from optical imaging of Ca signals in Purkinje cell dendrites. To construct the model from available voltage-clamp data, we first reproduced current-clamp records from a model isolated neuron (soma plus proximal dendrites). We next assumed that ionic channel kinetics in the dendrites were the same as in the soma. In accord with dendritic recordings and calcium-imaging data, we also assumed that significant g(Ca) occurs in dendrites. We then attached sections of basilar and apical dendritic cable. By trial and error, we found a distribution (not necessarily unique) of ionic conductance densities that was consistent with current-clamp records from the soma and dendrites of whole neurons and from isolated apical dendrites. The resulting model reproduces the Ca2+-dependent spike depolarizing afterpotential (DAP) recorded after a stimulus subthreshold for burst elicitation. The model also reproduces the behavior of CA3 pyramidal neurons injected with increasing somatic depolarizing currents: low-frequency (0.3-1.0 Hz) rhythmic bursting for small currents, with burst frequency increasing with current magnitude; then more irregular bursts followed by afterhyperpolarizations (AHPs) interspersed with brief bursts without AHPs; and finally, rhythmic action potentials without bursts. The model predicts the existence of still another firing pattern during tonic depolarizing dendritic stimulation: brief bursts at <1 to *q112 Hz, a pattern not observed during somatic stimulation. These bursts correspond to rhythmic dendritic calcium spikes. The model CA3 pyramidal neuron can be made to resemble functionally a CA1 pyramidal neuron by increasing ḡ(K(DR)) and decreasing dendritic ḡ(Ca) and ḡ(K(C)). Specifically, after these alterations, tonic depolarization of the soma leads to adapting repetitive firing, whereas stimulation of the distal dendrites leads to bursting. A critical set of parameters concerns the regulation of the pool of intracellular [Ca2+] that interacts with membrane channels (g(K(C)) and g(K(AHP))), particularly in the dendrites. For dendritic calcium spikes to occur at *q112 Hz, it appears necessary to postulate a time constant of <20 ms for decay of the intracellular [Ca2+] in this pool. This revised cellular model has been incorporated into a network of neurons with mutual excitation via both quisqualate and N-methyl-D-aspartate receptor types. Such a model network is able to reproduce picrotoxin-induced synchronized multiple bursts. Repetitive dendritic calcium spikes appear to be crucial for the phenomenon of multiple bursts.