G protein activation kinetics and spillover of-y-aminobutyric acid may account for differences between inhibitory responses in the hippocampus and thalamus ( synaptic transmission / neuromodulation / epilepsy )
We have developed a model of r-aminobutyric acid (GABA)ergic synaptic transmission mediated by GABAA and GABAB receptors, including cooperativity in the guanine nucleotide binding protein (G protein) cascade mediating the activation of K+ channels by GABAB receptors. If the binding of several G proteins is needed to activate the K+ channels, then only a prolonged activation of GABAB receptors evoked detectable currents. This could occur if strong stimuli evoked release in adjacent termipals and the spillover resulted in prolonged activatiod4of the receptors, leading to inhibitory responses similar to those observed in hippocampal slices. The same model also reproduced thalamic GABAB responses to high-frequency bursts of stimuli. In this case, prolonged activation of the receptors was due to highfrequency release conditions. This model provides insights into the function of GABAB receptors in normal and epileptic discharges. Two receptor types, GABAA and GABAB, are responsible for most inhibitory postsynaptic potentials (IPSPs) mediated by the release of y-aminobutyric acid (GABA) from presynaptic terminals. These receptors have characteristic differences in their kinetics (reviewed in refs. 1 and 2); GABAA-mediated currents have a relatively fast time course (time constant, 5-20 ms), whereas GABAB receptors induce much slower changes in the excitability of the cell (time constant, 150-200 ms). They differ as well in their activation. Typically, relatively strong stimulation is needed to evoke GABAB responses, whereas GABAA-mediated currents are evoked even for very low levels of presynaptic stimulation. Miniature GABAA IPSPs also occur spontaneously and are thought to arise from the spontaneous release of GABA from a single vesicle, but they never have a GABAB component (2-4). Physiological data on GABAergic responses show marked differences between thalamic and hippocampal slices. In the thalamus, stimulation of the reticular (RE) nucleus or interneurons induces biphasic GABAergic IPSPs in thalamocortical (TC) cells (5). The ratio between peak GABAA and GABAB currents evoked by RE neurons is insensitive to the intensity of the stimulation (6), but it changes markedly if the discharge of RE cells is enhanced by pharmacological means (6-9). In hippocampal slices, GABAergic currents can be elicited in the dendrites of pyramidal cells by stimulating interneurons in the stratum radiatum. Unlike the situation in thalamic cells, the GABAA/GABAB ratio depends critically on the intensity of the stimulation (10, 11) and on the presence of uptake (3, 12, 13). In this paper, we focus on the activation kinetics of GABAB responses, in which K+ channels are activated through a guanine nucleotide binding protein (G protein) cascade (14, 15). We assume that this activation shows some "cooperativity," in the sense that independent binding of several G-protein subunits is needed to open the K+ channels.