Abstract
Neurotransmitter dynamics within neuronal synapses can be controlled by astrocytes and reflect key contributors to neuronal activity. In particular, Glutamate (Glu) released by activated neurons is predominantly removed from the synaptic space by perisynaptic astrocytic transporters EAAT-2 (GLT-1). In previous work, we showed that the time course of Glu transport is affected by ionic concentration gradients either side of the astrocytic membrane and has the propensity for influencing postsynaptic neuronal excitability. Experimental findings co-localize GABA transporters GAT-3 with EAAT-2 on the perisynaptic astrocytic membrane. While these transporters are unlikely to facilitate the uptake of synaptic GABA, this paper presents simulation results which demonstrate the coupling of EAAT-2 and GAT-3, giving rise to the ionic-dependent reversed transport of GAT-3. The resulting efflux of GABA from the astrocyte to the synaptic space reflects an important astrocytic mechanism for modulation of hyperexcitability. Key results also illustrate an astrocytic-mediated modulation of synaptic neuronal excitation by released GABA at the glutamatergic synapse.
Highlights
Glutamate (Glu) and γ-aminobutyric acid (GABA) are the brain’s most prevalent excitatory and inhibitory neurotransmitters, respectively (Petroff, 2002)
Results are split into two sections: the first considers the resulting ionic changes due to the simulation while the second considers the effects of the neurotransmitter dynamics on the pre- and postsynaptic neuronal membrane
Considering this inverse behavior between intracellular and extracellular concentration change, these results suggest that the astrocytic efflux of K+ by EAAT-2 dominates over the influx of K+ by the Na+/K+ ATPase (NKA), with a net increase of [K+] in the cleft
Summary
Glutamate (Glu) and γ-aminobutyric acid (GABA) are the brain’s most prevalent excitatory and inhibitory neurotransmitters, respectively (Petroff, 2002). Exposure of neurons expressing appropriate excitatory ionotropic receptors, including N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs), to Glu can result in an influx of cations elevating the neuronal membrane potential toward the firing threshold (Meldrum, 2000). The exposure of neurons expressing GABA ionotropic receptors (GABAA-Rs) to GABA can result in a hyperpolarising current, decreasing the neuronal membrane potential away from the firing threshold (Sigel and Steinmann, 2012). EAAT-2 and GAT-3 Coupled Dynamics of Glu and GABA is an intracellular process, these neurotransmitters must be rapidly removed from the extracellular space (ECS) by their corresponding transporters, to avoid the over-exposure of the agonist to the excitatory and inhibitory ionotropic receptors (Petroff, 2002). Studies have indicated altered Glu and GABA concentrations within focal seizure sites (During and Spencer, 1993; Petroff, 2002), favoring excitatory neuronal behavior over inhibition
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