Keywords
Tripartite glutamatergic synapse, Astrocytic Glu/GABA exchange, Interplaying Glu-GABA transporters, GABA fluctuations, Tonic inhibitory feedback, Synaptic acuity
Abbreviations
Bestrophin 1: Homopentameric Ca2+-activated Cl− channel; EAAT2 (SLC1A2, GLT-1): Excitatory Amino Acid Transporter type 2 to Glu uptake in astrocytes by electrogenic 3Na+/Glu symport; GABAA receptor: Heteropentameric Cl− channel opened by GABA; GAT-3 (SLC6A11): GABA Transporter type 3 to astrocytic GABA uptake/release; GS: Gln Synthesize; MAOB: Key enzyme to astrocytic GABA production; SNAT3 (SLC38A3): Na+-coupled Neutral Amino acid Transporter type 3.
Commentary
Gliocentric paradigms showcase functional association of neurons with astrocytes, as in tripartite glutamatergic synapses. Astrocytes, activated by Glu:3Na(+) symport apply GABAergic inhibitory feedback on synaptic excitation via GABA efflux by GAT-3 reversal and subsequent GABAA activation (astrocytic Glu/GABA exchange [1-3]). Mechanistic models of astrocytic Glu/GABA exchange predict fluctuations of extrasynaptic GABA and tonic inhibitory feedback on synaptic signaling, integration, and hyperexcitability [4,5].
In tripartite glutamatergic synapses, extrasynaptic Glu activates astrocytic leaflet by Glu influx through EAAT2 Glu transporters [6]. Supported by Na+/K+-ATPase activity [7], EAAT2 performs electrogenic influx of 3 Na+ with 1 Glu in each transport sequence (3Na+:Glu symport). Spatiotemporal Na+ dynamics in the leaflet enable the reverse operation of nearby GABA transporter GAT-3, resulting in astrocytic efflux of 2Na+:GABA. The molecular mechanism, first described in 2009 by Héja and co-workers [1], allows for opening of extrasynaptic GABAA receptors, thus increasing tonic inhibitory feedback [2,3]. This astrocytic Glu/GABA exchange generates intrinsic fluctuations of Na+ and GABA along with GABA tone, contributing to synaptic plasticity [8].
Tonic inhibitory feedback on synaptic excitability, regulated by astrocytic Glu/GABA exchange is coupled to energy-dependent metabolic processes (Figure 1). Explicit molecular mechanism of astrocytic Glu/GABA exchange may relate gradients of extrasynaptic/cytosolic Na+, [Glu], [Gln], [GABA] and mitochondrial/cytosolic [GABA] to Na+:neurotransmitter transport rates (3Na+:Glu uptake, 2Na+:GABA release, 1Na+:Gln release/uptake). Emergent dynamics, described by partial differential-equations, determine the resulting oscillatory phase-transition. Also, model calculations correlating synaptic strength and astrocytic Glu/GABA exchange predict fluctuations of extracellular [GABA] [27]. We assume that alternating [GABA] brings about fluctuations of inhibitory feedback on input excitation, shaping spatiotemporal accuracy of synaptic signaling (acuity). The hypothesis may serve as a basis for diverse brain functions, for example sensory acuity [30] or cognitive-integration [33].
Figure 1: Scheme of tripartite glutamatergic synapse, presenting major players of astrocytic Glu/GABA exchange. Action potential activates presynaptic release of Glu and binding to postsynaptic Glu receptors. Extrasynaptic Glu is taken up by 3Na+:Glu symporter EAAT2 [6]. The enhancement of astrocytic Na+ reverses closest GABA transporter GAT-3 releasing 2Na+:GABA [3,9]. Released GABA activates extrasynaptic GABAA receptor, implementing tonic inhibitory feedback on synaptic excitation [1,2,10-28]. The astrocytic Glu/GABA exchange mechanism is coupled with key metabolic processes, including polyamine→GABA catabolism requiring MAOB [29-33], Glu metabolism to Gln by GS, and Glu-Gln recycling by Gln transporter SNAT3 [3,34-40].
Astrocytic release of GABA through inversed GAT-3 [41-43], but not Bestrophin-1 channel in brain areas such as cerebellum and hippocampus [44] suggests the emergence of astrocytic Glu/GABA exchange in these projection systems (Figure 2A vs. Figure 2B).
Figure 2: Comparison of glutamatergic synapses in cerebellar [45] and hippocampal [46-48] projection systems with signaling and integrating functions, respectively. (A) Scheme of olivo-cerebellar climbing fibers in the inferior olive–dentate nucleus region. Note synapses formed between mossy fibers and granule cells (granular layer: grey). (B) Hippocampal section comprising entorhinal-perforant path system. Recurrent projection system featured by synapses between i) entorhinal pyramidal cells (pyramids) and dentate gyrus granule cells (granules); ii) granules and CA3 hippocampal area pyramids; iii) pyramids of CA1 hippocampal area and ventral subiculum; iv) pyramids of ventral subiculum and entorhinal area.
Recognizing glutamatergic projection systems in cerebellar (Figure 2A) and hippocampal (Figure 2B) areas, we searched astrocytic Glu/GABA exchange using network approach [49]. Closely associated Glu-Gln recycling (Figure 1) data allege likely emergence of astrocytic Glu/GABA exchange [50-53].
Astrocytic Glu/GABA exchange is capable of affecting strength of hippocampal seizure-like activity, gamma-band oscillation [2], cognitive-integration [33] or cerebellar sensory acuity [30]. In addition, actual roles of astrocytic Glu/GABA exchange in neuroprotection [54], reward signaling-behavior [55], stroke [56], juvenile stress [40], epilepsy [57,58], Huntington's chorea [17,59] and Tourette-syndrome [22] have also been described. Broad and extensive participation of astrocytic Glu/GABA exchange characterizes the mechanism rather normal than unusual.
Acknowledgements
Authors thank Dr. Miklós Palkovits (Human Brain Bank, Semmelweis University, Budapest) for suggestions about glutamatergic synapses in cerebellar and hippocampal projection systems.
Author Contribution
JK and LH wrote the manuscript, LH designed the figures.
Conflicts of Interest
The authors declare no competing interests.
Funding
This work was supported by National Research, Development and Innovation Office grant OTKA K124558. László Héja is a recipient of the János Bolyai Scholarship of the Hungarian Academy of Sciences.
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