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Commentary Open Access
Volume 1 | Issue 1 | DOI: https://doi.org/10.46439/signaling.1.016

GABA fluctuations driven by astrocytic Glu-GABA exchange explain synaptic acuity

  • 1HUN-REN Research Centre for Natural Sciences, Budapest, Hungary
+ Affiliations - Affiliations

*Corresponding Author

 Julianna Kardos, kardos.julianna@ttk.hu

Received Date: September 16, 2023

Accepted Date: October 27, 2023

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].

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).

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.

References

1. Héja L, Barabás P, Nyitrai G, Kékesi KA, Lasztóczi B, Tőke O, et al. Glutamate uptake triggers transporter-mediated GABA release from astrocytes. PloS One. 2009 Sep 24;4(9):e7153.

2. Héja L, Nyitrai G, Kékesi O, Dobolyi Á, Szabó P, Fiáth R, et al. Astrocytes convert network excitation to tonic inhibition of neurons. BMC Biology. 2012 Dec;10(1):1-21.

3. Héja L, Simon Á, Szabó Z, Kardos J. Feedback adaptation of synaptic excitability via Glu: Na+ symport driven astrocytic GABA and Gln release. Neuropharmacology. 2019 Dec 15;161:107629.

4. Gavrilov N, Golyagina I, Brazhe A, Scimemi A, Turlapov V, Semyanov A. Astrocytic coverage of dendritic spines, dendritic shafts, and axonal boutons in hippocampal neuropil. Frontiers in Cellular Neuroscience. 2018 Aug 17;12:248.

5. Lalo U, Koh W, Lee CJ, Pankratov Y. The tripartite glutamatergic synapse. Neuropharmacology. 2021 Nov 1;199:108758.

6. Rusakov DA, Stewart MG. Synaptic environment and extrasynaptic glutamate signals: The quest continues. Neuropharmacology. 2021 Sep 1;195:108688.

7. Rose EM, Koo JC, Antflick JE, Ahmed SM, Angers S, Hampson DR. Glutamate transporter coupling to Na, K-ATPase. Journal of Neuroscience. 2009 Jun 24;29(25):8143-55.

8. Dityatev A, Rusakov DA. Molecular signals of plasticity at the tetrapartite synapse. Current Opinion in Neurobiology. 2011 Apr 1;21(2):353-9.

9. Melone M, Ciappelloni S, Conti F. A quantitative analysis of cellular and synaptic localization of GAT-1 and GAT-3 in rat neocortex. Brain Structure and Function. 2015 Mar;220:885-97.

10. Lee M, McGeer EG, McGeer PL. Mechanisms of GABA release from human astrocytes. Glia. 2011 Nov;59(11):1600-11.

11. Kirischuk S, Parpura V, Verkhratsky A. Sodium dynamics: another key to astroglial excitability?. Trends in Neurosciences. 2012 Aug 1;35(8):497-506.

12. Brickley SG, Mody I. Extrasynaptic GABAA receptors: their function in the CNS and implications for disease. Neuron. 2012 Jan 12;73(1):23-34.

13. Min R, Santello M, Nevian T. The computational power of astrocyte mediated synaptic plasticity. Frontiers in Computational Neuroscience. 2012 Nov 1;6:93.

14. Kersanté F, Rowley SC, Pavlov I, Gutièrrez‐Mecinas M, Semyanov A, Reul JM, et al. A functional role for both γ‐aminobutyric acid (GABA) transporter‐1 and GABA transporter‐3 in the modulation of extracellular GABA and GABAergic tonic conductances in the rat hippocampus. The Journal of Physiology. 2013 May;591(10):2429-41.

15. Rose CR, Karus C. Two sides of the same coin: sodium homeostasis and signaling in astrocytes under physiological and pathophysiological conditions. Glia. 2013 Aug;61(8):1191-205.

16. Unichenko P, Dvorzhak A, Kirischuk S. Transporter‐mediated replacement of extracellular glutamate for GABA in the developing murine neocortex. European Journal of Neuroscience. 2013 Dec;38(11):3580-8.

17. Wójtowicz AM, Dvorzhak A, Semtner M, Grantyn R. Reduced tonic inhibition in striatal output neurons from Huntington mice due to loss of astrocytic GABA release through GAT-3. Frontiers in Neural Circuits. 2013 Nov 26;7:188.

18. Wlodarczyk AI, Xu C, Song I, Doronin M, Wu YW, Walker MC, et al. Tonic GABAA conductance decreases membrane time constant and increases EPSP-spike precision in hippocampal pyramidal neurons. Frontiers in Neural Circuits. 2013 Dec 25;7:205.

19. Losi G, Mariotti L, Carmignoto G. GABAergic interneuron to astrocyte signalling: a neglected form of cell communication in the brain. Philosophical Transactions of the Royal Society B: Biological Sciences. 2014 Oct 19;369(1654):20130609.

20. DiNuzzo M, Mangia S, Maraviglia B, Giove F. Physiological bases of the K+ and the glutamate/GABA hypotheses of epilepsy. Epilepsy Research. 2014 Aug 1;108(6):995-1012.

21. Rae CD. A guide to the metabolic pathways and function of metabolites observed in human brain 1 H magnetic resonance spectra. Neurochemical Research. 2014 Jan;39:1-36.

22. Jackson GM, Draper A, Dyke K, Pépés SE, Jackson SR. Inhibition, disinhibition, and the control of action in Tourette syndrome. Trends in Cognitive Sciences. 2015 Nov 1;19(11):655-65.

23. Schitine CS, Mendez-Flores OG, Santos LE, Ornelas I, Calaza KC, Pérez-Toledo K, et al. Functional plasticity of GAT-3 in avian Müller cells is regulated by neurons via a glutamatergic input. Neurochemistry International. 2015 Mar 1;82:42-51.

24. Kirischuk S, Héja L, Kardos J, Billups B. Astrocyte sodium signaling and the regulation of neurotransmission. Glia. 2016 Oct;64(10):1655-66.

25. Rose CR, Verkhratsky A. Principles of sodium homeostasis and sodium signalling in astroglia. Glia. 2016 Oct;64(10):1611-27.

26. Mederos S, Perea G. GABAergic‐astrocyte signaling: a refinement of inhibitory brain networks. Glia. 2019 Oct;67(10):1842-51.

27. Flanagan B, McDaid L, Wade JJ, Toman M, Wong-Lin K, Harkin J. A computational study of astrocytic GABA release at the glutamatergic synapse: EAAT-2 and GAT-3 coupled dynamics. Frontiers in Cellular Neuroscience. 2021 Jul 12;15:682460.

28. Ueberbach T, Simacek CA, Tegeder I, Kirischuk S, Mittmann T. Tonic activation of GABAB receptors via GAT-3 mediated GABA release reduces network activity in the developing somatosensory cortex in GAD67-GFP mice. Frontiers in Synaptic Neuroscience. 2023 May 30;15:1198159.

29. Yoon BE, Woo J, Chun YE, Chun H, Jo S, Bae JY, An H, Min JO, Oh SJ, Han KS, Kim HY. Glial GABA, synthesized by monoamine oxidase B, mediates tonic inhibition. The Journal of Physiology. 2014 Nov 15;592(22):4951-68.

30. Kwak H, Koh W, Kim S, Song K, Shin JI, Lee JM, et al. Astrocytes control sensory acuity via tonic inhibition in the thalamus. Neuron. 2020 Nov 25;108(4):691-706.

31. Kovács Z, Skatchkov SN, Veh RW, Szabó Z, Németh K, Szabó PT, et al. Critical Role of Astrocytic Polyamine and GABA Metabolism in Epileptogenesis. Frontiers in Cellular Neuroscience. 2022 Jan 6;15:787319.

32. Kilb W, Kirischuk S. GABA release from astrocytes in health and disease. International Journal of Molecular Sciences. 2022 Dec 13;23(24):15859.

33. W. Koh, H. Kwak, E. Cheong, C.J. Lee, GABA tone regulation and its cognitive functions in the brain, Nat. Rev. Neurosci. 24 (2023) 523-539. https://doi.org/10.1038/s41583-023-00724-7.

34. Schousboe A, Bak LK, Waagepetersen HS. Astrocytic control of biosynthesis and turnover of the neurotransmitters glutamate and GABA. Frontiers in Endocrinology. 2013 Aug 15;4:102.

35. Tani H, Dulla CG, Farzampour Z, Taylor-Weiner A, Huguenard JR, Reimer RJ. A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release. Neuron. 2014 Feb 19;81(4):888-900.

36. Overstreet-Wadiche L, Wadiche JI. Good housekeeping. Neuron. 2014 Feb 19;81(4):715-7.

37. Hertz L, Rothman DL. Glucose, lactate, β-hydroxybutyrate, acetate, GABA, and succinate as substrates for synthesis of glutamate and GABA in the glutamine–glutamate/GABA cycle. The glutamate/GABA-glutamine cycle: Amino Acid Neurotransmitter Homeostasis. 2016:9-42.

38. Todd AC, Marx MC, Hulme SR, Bröer S, Billups B. SNAT3‐mediated glutamine transport in perisynaptic astrocytes in situ is regulated by intracellular sodium. Glia. 2017 Jun;65(6):900-16.

39. Schousboe A. Metabolic signaling in the brain and the role of astrocytes in control of glutamate and GABA neurotransmission. Neuroscience letters. 2019 Jan 10;689:11-3.

40. Ivens S, Çalışkan G, Papageorgiou I, Cesetti T, Malich A, Kann O, et al. Persistent increase in ventral hippocampal long‐term potentiation by juvenile stress: a role for astrocytic glutamine synthetase. Glia. 2019 Dec;67(12):2279-93.

41. Bheemanapally K, Napit PR, Ibrahim MM, Briski KP. UHPLC–electrospray ionization–mass spectrometric analysis of brain cell-specific glucogenic and neurotransmitter amino acid content. Scientific Reports. 2021 Aug 9;11(1):16079.

42. Kofuji P, Araque A. G-protein-coupled receptors in astrocyte–neuron communication. Neuroscience. 2021 Feb 21;456:71-84.

43. Verkhratsky A. Untangling complexities of glial-neuronal communications: astroglial metabolic cascades orchestrate tonic inhibition in the thalamus. Neuron. 2020 Nov 25;108(4):585-7.

44. Ormel L, Lauritzen KH, Schreiber R, Kunzelmann K, Gundersen V. GABA, but not Bestrophin-1, is localized in astroglial processes in the mouse hippocampus and the cerebellum. Frontiers in Molecular Neuroscience. 2020 Jul 28;13:135.

45. Llinás RR. The olivo-cerebellar system: a key to understanding the functional significance of intrinsic oscillatory brain properties. Frontiers in Neural Circuits. 2014 Jan 28;7:96.

46. Amaral DG, Witter MP. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience. 1989 Jan 1;31(3):571-91.

47. Sloviter RS, Lømo T. Updating the lamellar hypothesis of hippocampal organization. Frontiers in Neural Circuits. 2012 Dec 10;6:102.

48. Oliva A, Fernandez-Ruiz A, KarabaLA. CA2 orchestrates hippocampal network dynamics. Hippocampus. 2023;33:241-51.

49. Jeong H, Tombor B, Albert R, Oltvai ZN, Barabási AL. The large-scale organization of metabolic networks. Nature. 2000 Oct 5;407(6804):651-4.

50. Erö C, Gewaltig MO, Keller D, Markram H. A cell atlas for the mouse brain. Frontiers in Neuroinformatics. 2018 Nov 28;12:84.

51. Rodarie D, Verasztó C, Roussel Y, Reimann M, Keller D, Ramaswamy S, et al. A method to estimate the cellular composition of the mouse brain from heterogeneous datasets. PLOS Computational Biology. 2022 Dec 21;18(12):e1010739.

52. Roussel Y, Verasztó C, Rodarie D, Damart T, Reimann M, Ramaswamy S, et al. Mapping of morpho-electric features to molecular identity of cortical inhibitory neurons. PLOS Computational Biology. 2023 Jan 5;19(1):e1010058.

53. Shichkova P, Coggan JS, Markram H, Keller D. A standardized brain molecular atlas: a resource for systems modeling and simulation. Frontiers in Molecular Neuroscience. 2021:604559.

54. Kardos J, Heja L, Jemnitz K, Kovacs R, Palkovits M. The nature of early astroglial protection—Fast activation and signaling. Progress in Neurobiology. 2017 Jun 1;153:86-99.

55. Kardos J, Dobolyi Á, Szabó Z, Simon Á, Lourmet G, Palkovits M,et al. Molecular plasticity of the nucleus accumbens revisited—astrocytic waves shall rise. Molecular Neurobiology. 2019 Dec;56:7950-65.

56. Lie ME, Al-Khawaja A, Damgaard M, Haugaard AS, Schousboe A, Clarkson AN, Wellendorph P. Glial GABA transporters as modulators of inhibitory signalling in epilepsy and stroke. Glial Amino Acid Transporters. 2017:137-67.

57. Héja L. Astrocytic target mechanisms in epilepsy. Current Medicinal Chemistry. 2014 Feb 1;21(6):755-63.

58. Kardos J, Szabó Z, Héja L. Framing Neuro-Glia Coupling in Antiepileptic Drug Design: Miniperspective. Journal of Medicinal Chemistry. 2016 Feb 11;59(3):777-87.

59. Khakh BS, Beaumont V, Cachope R, Munoz-Sanjuan I, Goldman SA, Grantyn R. Unravelling and exploiting astrocyte dysfunction in Huntington’s disease. Trends in Neurosciences. 2017 Jul 1;40(7):422-37.

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