Ionic mechanisms underlying spontaneous CA1 neuronal firing in Ca2+-free solution

Abstract

Hippocampal CA1 neurons exposed to zero-[Ca(2+)] solutions can generate periodic spontaneous synchronized activity in the absence of synaptic function. Experiments using hippocampal slices showed that, after exposure to zero-[Ca(2+)](0) solution, CA1 pyramidal cells depolarized 5-10 mV and started firing spontaneous action potentials. Spontaneous single neuron activity appeared in singlets or was grouped into bursts of two or three action potentials. A 16-compartment, 23-variable cable model of a CA1 pyramidal neuron was developed to study mechanisms of spontaneous neuronal bursting in a calcium-free extracellular solution. In the model, five active currents (a fast sodium current, a persistent sodium current, an A-type transient potassium current, a delayed rectifier potassium current, and a muscarinic potassium current) are included in the somatic compartment. The model simulates the spontaneous bursting behavior of neurons in calcium-free solutions. The mechanisms underlying several aspects of bursting are studied, including the generation of triplet bursts, spike duration, burst termination, after-depolarization behavior, and the prolonged inactive period between bursts. We show that the small persistent sodium current can play a key role in spontaneous CA1 activity in zero-calcium solutions. In particular, it is necessary for the generation of an after-depolarizing potential and prolongs both individual bursts and the interburst interval.

FIGURE 1

Structure of CA1 pyramidal cell model.

FIGURE 2

Steady-state curves (solid line) and time-constant curves (dotted line) for the model ionic channels: gates m and h for I_Na; a and b for I_A; n for I_DR; u for I_M; and w for I_NaP.

FIGURE 3

(A) Typical spontaneous intracellular recording of a triplet observed in vitro in zero-calcium conditions, and (B), the triplet action potential generated by the model using parameters (given in Table 1) without any stimulus.

FIGURE 4

Detailed curves of various currents during a burst for the CA1 model. (Bottom to top) (A) The transmembrane potential in the somatic compartment. (B) The total current I_Total in the somatic compartment. (C) The dominant inward currents I_Na with dashed line and the dominant outward current I_A with solid line. (D) Persistent sodium current I_NaP. (E) The potassium currents I_DR with solid line and I_M with dashed line. (F) The axial current I_Soma-Den between the somatic compartment and the two neighboring dendritic compartments. Five of six peaks for current I_Total in B are clipped by the frame. The first peak for current I_Soma-Den in F is also clipped.

FIGURE 5

(A) Intracellular recording observed for an HPC in vitro in zero-calcium condition with different depolarizing DC currents applied intracellularly. (B) Model cell behavior at different DC depolarizing currents. Both show that the addition of a depolarizing DC current results in a transition from triplet activity, to doublets and then singlets. (C) A complex activity with varying burst patterns can be observed for the model with 0.04-nA depolarizing DC current. (D) The spiking frequencies both in vitro (square) and in the model (circle) increases as the DC stimulus are increased. The spiking frequency is calculated as the average spiking rate over time. The variance for frequency in vitro is 2; for the model, <0.2. The suppression of spike firing occurs at large enough depolarizing or hyperpolarizing currents. In the upper part of D, the typical regions of different spiking number per burst are also indicated. Here 1S, 2S, and 3S mean singlet, doublet, and triplet modes of activity, respectively. The activity of a two-spike burst followed by a three-spike burst is simply indicated by 5S. CS refers to the complex burst mode.

FIGURE 6

(A) Spiking frequency of the CA1 model with the change in conductance g_NaP (circle) and g_Na (square). Too large or too small g_NaP blocks spiking activity. In the upper part of A, the typical regions of different spiking number per burst are shown for the change of g_NaP. (B) A decrease of g_NaP results in a reduction of the prolonged ADP after the action potentials in a triplet or doublet burst. (C) A notable delay in the appearance of the third spike for the burst is induced by a decrease of g_NaP.

FIGURE 7

Effect of varying g_Na on burst activity for the CA1 model. (A) A periodic six-spike burst can be obtained with 130% g_Na. (B) The spiking number per burst increases with the increase of g_Na. (C) Decrease or increase of g_Na results in ADP reduction or prolongation, and (D), the delay of the final spike in the burst.

FIGURE 8

Effect of increased [K⁺]_o on the spiking frequency with the model in the single HPC level. An increase of [K⁺]_o results in an increase of the potassium reversal potential, as well as the potassium currents. (A) The action potential for the model cell with different [K⁺]_o. (B) The average interspike frequencies in the model (circle) increases as [K⁺]_o increases in a certain region. In the upper part of B, typical regimes with different burst modes are indicated.

FIGURE 9

Spiking frequency of the CA1 model with the change in conductance g_A, g_DR, and g_M of potassium currents. A decrease of potassium current conductance results in an increase of the spiking frequency in a certain region. In each figure, the typical regimes with different burst modes are also indicated.