Giant glial cell: new insight through mechanism-based modeling

Abstract

The paper describes a detailed mechanism-based model of a tripartite synapse consisting of P- and R-neurons together with a giant glial cell in the ganglia of the medical leech (Hirudo medicinalis), which is a useful object for experimental studies in situ. We describe the two main pathways of the glial cell activation: (1) via IP(3) production and Ca(2 +) release from the endoplasmic reticulum and (2) via increase of the extracellular potassium concentration, glia depolarization, and opening of voltage-dependent Ca(2 +) channels. We suggest that the second pathway is the more significant for establishing the positive feedback in glutamate release that is critical for the self-sustained activity of the postsynaptic neuron. This mechanism differs from the mechanisms of the astrocyte-neuron signaling previously reported.

Fig. 1

Illustration of the tripartite synapse with its P- and R-neurons and the GGC (color on-line only). Blue circles represent glutamate (Glu) released from presynaptic P-neuron under excitation. Glutamate interacts with ionotropic receptors (i-GluR) of the R-neuron and metabotropic receptors (m-GluR) of the GGC. Activation of m-GluRs results in IP₃ production and opening of IP₃-receptors (IP₃R). Grey circles are glutamate released from the glial cell during increases in the cytosolic Ca^2 + concentration above a certain threshold. The main entry of Ca^2 + into the glial cytoplasm occurs via Ca^2 +-channels. “Glial” glutamate interacts with both i-GluRs of the R-neuron and m-GluRs of the glial cell. For a detailed description, see the main text

Fig. 2

Time course for the model variables (from top to the bottom): transmembrane voltage V_P and V_R for P and R neurons, respectively; extracellular glutamate concentration [Glu]; extracellular potassium concentration [K]_W; glial cell membrane potential V_G; glial cytosolic calcium [Ca]; and the intraglial IP₃ concentration. The filled horizontal bar above the top panel indicates the duration of the external stimulus applied to the P-neuron

Fig. 3

With unblocked glutamate production by the glial cell, a short stimulation of the P-neuron does not result in a glial calcium response (top panels), while the longer stimulation triggers glial glutamate release and evokes self-sustained neuronal firing (bottom panels). Dotted curves in the bottom panels show the glial and neuronal response at 8% lower sensitivity of the R-neuron to the extracellular glutamate concentration

Fig. 4

At longer time scales, the self-sustained firing of the R-neuron is terminated as the glial glutamate store is emptied