Rodinskiy А. G., Demchenko T. V., Romanenko L. A.

LITERATURE REVIEWS

Scentific article

The γ-aminobutyric acid (GABA) is dominant inhibitory neurotransmitter in the CNS. By opening Cl-channels, GABA generally hyperpolarizes the membrane potential, decreases neuronal activity, and reduces intra-cellular Ca2+ of mature neurons. GABA, which is the principal excitatory transmitter in the developing brain, acts as an epigenetic factor to control processes including cell proliferation, neuroblast migration and dendritic maturation. These effects appear to be mediated through a paracrine, diffuse, non-synaptic mode of action that precedes the more focused, rapid mode of operation characteristic of synaptic connections. This sequential operation implies that GABA is used as an informative agent but in a unique context at an early developmental stage. GABA is the first neurotransmitter to become functional in developing networks and provides most of the initial excitatory drive. GA-BA-mediated mechanisms thus have a central role both in early stages This review will examine the roles of GABA, particularly in relation to proliferation, neuronal migration, synapse formation and activity-dependent mechanisms that are essential for network construction. GABA increases the proliferation of cerebellar granule cell precursors. For these actions, GABA functions in association with various trophic factors. In maturing brain, GABA exerts a de-polarizing action related namely to a reverse gradient of Cl-. This transient effect is essentially due to a low expres- sion of the neuronal Cl–extruding K+/ Cl- co-transporter KCC2. There is general agreement that the GABA switch from excitatory to inhibitory action is mediated by upregulation of the cotransporter KCC2, which extrudes Cl- and has delayed expression. GABA has a variety of important functions during maturation. The uniqueness of GABA is epitomized by its early operation–before glutamate synapses are functional – indicating that, at least during a restricted period, GABA provides all the excitatory drive. In addition, the possibly activity dependent shift of GABA actions following upregulation of KCC2 provides a remarkable modulation of the set-point at which GABA will re-sume its classical inhibitory effects. In the adult mammalian brain, GABA – releasing synapses (the principal source of inhibition) and synapses that use glutamate (the principal excitatory transmitter) operate through ionotropic re-ceptor channels that are permeable to anions and cations, respectively. GABA is initially excitatory as a result of a high ([Cl–]i). GABA-releasing and glutamatergic synapses are formed sequentially. There is a primitive network-driven pattern of electrical activity in all developing circuits – the giant depolarizing potentials (GDPs), which are generated in part by the excitatory actions of GABA. This pattern allows the generation of large oscillations of intra-cellular calcium, even in neurons that have few synapses, and an activity dependent modulation of neuronal growth and synapse formation. Later on, once a sufficient density of glutamate and GABA synapses has been generated and inhibition becomes necessary, a chloride-extruding system becomes operative, an event that seems to be ac-tivity dependent. As a result, chloride is efficiently pumped from the intracellular, GABA begins to exert its inhibitory action, and the primitive pattern is replaced by more diverse and elaborate patterns of activity. The main steps of this cascade, including the shift from excitatory to inhibitory actions of GABA, are modulated by neuronal activity. After neuronal trauma, GABA, both synaptically released and exogenously applied, exerted a novel and opposite effect, depolarizing neurons and increasing intracellular Ca2+. So, this story leaves us with more questions than answers.

GABA, glutamate, calcium, chloride.

• 1. Andersen P. Two different responses of hippocampal pyramidal cells to application of GABA/ P. Andersen //J. Physiol. – 1980. – Vol. 305. – P. 279 -296.
• 2. Asada H. Cleft palate and decreased brain GABA in mice lacking the 67-kDa isoform of glutamic acid decarboxylase / H. Asada, y. Kawamura // Proc. Natl. Acad. Science USA. – 1997. – Vol. 94. – P. 6496-6499.
• 3. Bading H. Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways / H. Bading, D. Ginty, M. Greenberg // Science. – 1993. – Vol. 260, №5105. – P. 181-186.
• 4. Behar T. N. GABA stimulates chemotaxis and chemokinesis of embryonic cortical neurons via calcium-dependent mecha-nisms / T. N. Behar, y. X. Li, H. T. Tran [et al.] // J. Neurosci. – 1996. – Vol. 16, №5. – P. 1808-1818.
• 5. Behar T. N. GABA receptor antagonists modulate postmitotic cell migration in slice cultures of embryonic rat cortex / A. E. Schaffner, C. A. Scott [et al.] // Cereb. Cortex. – 2000. – Vol. 10, №9. – P. 899-909.
• 6. Behr J. Kindling enhances kainate receptor-mediated depression of GABAergic inhibition in rat granule cells / J. Behr, C. Gebhardt, U. Heinemann // Eur. J. Neuroscience. – 2002. – Vol. 16, №5. – P. 861–867.
• 7. Belhage B. Effect of GABA on synaptogenesis and synaptic function/ B. Belhage, G. H. Hansen, L. Elster, [et al.] // Perspectives on Developmental Neurobiology. – 1998. – Vol. 5, №2-3. – P. 235-242.
• 8. Ben Ari y. Excitatory actions of GABA during development: the nature of the nurture / y. Ben Ari // J. Neurosci. – 2002. – Vol. 3, №9. – P. 658–739.
• 9. Ben Ari y. GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations / y. Ben Ari // Physiol. Rev. – 2007. – Vol. 87, №4. – P. 1215–1284.
• 10. Ben-Ari y. Trophic actions of GABA on neuronal development / y. Ben-Ari, A. Represa // Trends Neurosci. – 2005. – Vol. 28, №6. – P. 278-283.
• 11. Bettler B. Molecular structure and physiological functions of GABAB receptors / B. Bettler, K. Kaupmann // Physiol. Rev. – 2004. – Vol. 84, №3. – P. 835–867.
• 12. Boistel J. Membrane permeability change during inhibitory transmitter action in crustacean muscle / J. Boistel // J. Physiol. – 1958. – Vol. 144, №1. – P. 167-191.
• 13. Chen G. Excitatory actions of GABA in rat developing hypothalamic neurones / G. Chen, P. Q. Trombley, A. N. Pol // J. Physiol.– 1996. – Vol. 494. – P. 451–454.
• 14. Cherubini E. GABA: an excitatory transmitter in early postnatal life / E. Cherubini, J. L. Gaiarsa // Trends in Neuroscience. – 1991. – Vol. 14, №12. – P. 515–519.
• 15. Cherubini E. GABA mediated excitation in immature rat CA3 hippocampal neurons / E. Cherubini, C. Rovira, J. L. Gaiarsa // International J. of Developmental Neuroscience. – 1990. – Vol. 8, №4. – P. 481– 490.
• 16. Curtis D. R. The depression of spinal neurones by γ-amino-n-butyric acid and β-alanine / D. R. Curtis, J. W. Phillis // J. Physi-ol. – 1959. – Vol. 1, №1. – P. 185–203.
• 17. Devlin C. L. The pharmacology of GABA and acetylcholine receptors at the echinoderm neuromuscular junction / C. L. Dev-lin // J. Experimental Biology. – 2001. – Vol. 204, №5. – P. 887–896.
• 18. Devlin C. L. Pharmacological identification of acetylcholine receptor subtypes in echinoderm smooth muscle / C. L. Devlin, W. Schlosser, D. T. Belz // Comp. Biochem. Physiol. – 2000. – Vol. 125C. – P. 53–64.
• 19. Elphick M. R. Neuropeptide structure and function in echinoderms / M. R. Elphick // PhD Thesis, Royal Holloway and Bedford New College. – 1991. – 245 р.
• 20. Engel D. Plasticity of rat central inhibitory synapses through GABA metabolism / D. Engel // Journal of Physiology. – 2001. – Vol. 535, №2. – P. 473–482.
• 21. Federico T. F. Enhancement of GABA Release through еndogenous аctivation of axonal gabaa receptors in juvenile cere-bellum / T. F. Federico, A. Marty // J. Neurosci. – 2007. – Vol. 27, №12. – P. 119-123.
• 22. Fiszman M. L. GABA induces proliferation of immature cerebellar granule cells grown / M. L. Fiszman //Brain Res. – 1999. – Vol. 115, №1. – P. 1-8.
• 23. Florey E. An inhibitory and an excitatory factor of mammalian CNS, and their action on a single sensory neuron / E. Florey // Arch. Int. Physiol. – 1954. – Vol. 62, №1. – P. 33–53.
• 24. Florey E. Excitatory actions of GABA and of acetylcholine in sea urchin tube feet / Е. Florey // Comp. Biochem. Physiol. – 1975. – Vol. 51C. – P. 5–12.
• 25. Franklin J. L. Suppression of programmed neuronal death by sustained elevations of cytoplasmic calcium / J. L. Franklin, E. M. Johnson // Trends Neurosci. – 1992. – Vol. 15, №12. – P. 501-508.
• 26. Fritsch B. Pathological alterations in GABAergic interneurons and reduced tonic inhibition in the basolateral amygdala during epileptogenesis / B. Fritsch, F. Qashu // Neuroscience. – 2009. – Vol. 163, №1. – P. 415–429.
• 27. Galanopoulou A. S. The epileptic hypothesis: developmentally related arguments based on animal models / A. S. Galanopoulou, S. L. Moshe // Epilepsia, – 2009. – Vol. 7, №50. – P. 37–42.
• 28. Ganguly K. GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition / K. Ganguly, A. F. Schinder, S. T. Wong // Cell. – 2001. – Vol. 105, №4. – P. 521-532.
• 29. Gao X. -B. GABA release from mouse axonal growth cones / X. -B. Gao, A. N. Pol // Journal of Physiology. – 2000. – Vol. 523, №3. – P. 629-637.
• 30. Gascon E. Potentially toxic effects of anaesthetics on the developing central nervous system / E. Gascon, P. Klauser, J. Z. Kiss // European Journal of Anaesthesiology. – 2007. – Vol. 24, №3. – P. 213-224.
• 31. Grattan D. R. GABAergic neuronal activity and mRNA levels for both forms of glutamic acid decarboxylase are reduced in the diagonal band of Broca during the afternoon of proestrus / D. R. Grattan, M. S. Rocca //Brain Research. – 1996. – Vol. 733, №1. – P. 50–55.
• 32. Hensch T. K. Critical period plasticity in local cortical circuits / T. K. Hensch // Nature Reviews Neuroscience. – 2005. – Vol. 6, №11. – P. 877-888 (2005).
• 33. Hensch T. K. Critical period regulation, / T. K. Hensch // Annual Review of Neuroscience. – 2004. – Vol. 27. – P. 549-579.
• 34. Hensch T. K. Local GABA circuit control of experience-dependent plasticity in developing visual cortex / T. K. Hensch, M. Fa-giolini, N. Mataga // Science. – 1998 – Vol. 282, №5393. – P. 1504-1508.
• 35. Hubner C. Disruption of KCC2 reveals an essential role of K-Cl-cotransport already in early synaptic inhibition / C. Hubner, V. Stein // Neuron. – 2001. – Vol. 30, №2. – P. 515–524.
• 36. Jentsch T. J. Molecular structure and physiological function of chloride channels / T. J. Jentsch // Physiol. Rev. – 2002. – Vol. 82, №2. – P. 503-568.
• 37. Jursky F. Structure, function and brain localization of neurotransmitter transporters / F. Jursky, S. Tamura // J. Exp. Biol. – 1994. – Vol. 196. – P. 283–295.
• 38. Kaila K. Influence of GABA-gated bicarbonate conductance on potential, current and intracellular chloride in crayfish muscle fibres / K. Kaila, M. Pasternack, J. Saarikoski // J. Physiol. – 1989. – Vol. 416. – P. 161-181.
• 39. Kaila K. Postsynaptic fall in intracellular pH induced by GABA-activated bicarbonate / K. Kaila, J. Voipio // Nature. – 1987. – Vol. 330. – P. 163-165.
• 40. Kobzar G. T. Muscle chemoreceptors in the holothurians / G. T. Kobzar // J. of Evolut. Biochem. and Physiol. – 1984. –Vol. 20, №1. – P. 419–422.
• 41. Krnjevi K. When and why amino acids? / K. Krnjevi // J. Physiol. – 2010. – Vol. 588, №1. – P. 33–44.
• 42. Luhmann H. J. Postnatal maturation of the GABAergic system in rat neocortex / H. J. Luhmann, D. A. Prince // J. Neurophysiol.– 1991. – Vol. 65, №2. – P. 247-263.
• 43. Lujan R. Glutamate and GABA receptor signalling in the developing brain / R. Lujan // Neuroscience. – 2005. – Vol. 130, №3.– P. 567-580.
• 44. McNamara J. O. Cellular and molecular basis of epilepsy / J. O. McNamara // J. Neoroscience. 1994. – Vol. 6, №14. – P. 3413–3425.
• 45. Murphy D. D. Estradiol increases dendritic spine density by reducing GABA neurotransmission in hippocampal neurons / D. D. Murphy // Journal of Neuroscience. 1998. – Vol. 18, №7. – P. 2550–2559.
• 46. Nguyen L. Neurotransmitters as early signals for CNS development / L. Nguyen // Cell Tissue Res. – 2001. – Vol. 305, №2. – P. 187-202.
• 47. Obrietan K. GABA neurotransmission in the hypothalamus: developmental transition from Ca2+ excitatory to inhibitory / K. Obrietan, A. N. Pol // J. Neuroscience. 1995. – Vol. 15, №7. – P. 5065–5077.
• 48. Obrietan K. Growth cone calcium rise evoked by GABA / K. Obrietan, A. N. Pol // J. Comp. Neurol. –1996. – Vol. 365, №2. – P. 167-175.
• 49. Olney J. W. New insights and new issues in neurotoxicology / J. W. Olney // Neurotoxicology. – 2002. -Vol. 23, №6. – P. 659-668.
• 50. Owens D. F. Excitatory GABA responses in embryonic and neonatal cortical slices demonstrated by gramicidin perforated-patch recordings / D. F. Owens // J. Neuroscience. 1996. – Vol. 16, №20. – P. 6414–6423.
• 51. Owens D. F. Developmental neurotransmitters? / D. F. Owens, A. R. Kriegstein // Neuron. – 2002. – Vol. 36, №6. – P. 989-991. 52. Pol A. N. Excitatory actions of GABA after neuronal trauma / A. N. Pol, K. Obrietan // J. Neuroscience. – 1996. – Vol. 16,№13. – P. 4283-4292.
• 53. Reichling D. B. Mechanisms of GABA and glycine depolarization-induced calcium transients in rat dorsal horn neurons / D. B. Reichling, A. Kyrozis, J. Wang // J. Physiol. 1994. – Vol. 476, №3. – P. 411–421.
• 54. Rekling J. C. Synaptic control of motoneuronal excitability / J. C. Rekling, G. D. Funk // Physiological Reviews. – 2000. – Vol. 80, №2. – P. 767-852.
• 55. Rivera C. Two developmental switches in GABAergic signalling / C. Rivera, J. Voipio, K. Kaila // J. Physiol. 2005. – Vol. 562, №1. – P. 27-36.
• 56. Rivera C. The K/Cl co-transporter renders GABA hyperpolarizing during neuronal maturation / C. Rivera // Nature. – 1999. – Vol. 397. – P. 251–255.
• 57. Rohrbough J. Regulation of intracellular Cl- levels by Na+-dependent Cl- cotransport distinguishes depolarizing from hyperpolarizing GABAA receptor responses / J. Rohrbough // J. Neurosci. – 1996. – Vol. 16, №1. – P. 82–91.
• 58. Snead O. C. Gamma-hydroxybutyrate model of generalized absence seizures: further characterization and comparison withother absence models / O. C. Snead // Epilepsia. – 1988. – Vol. 29, №4. – P. 361–364.
• 59. Staley K. J. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors / K. J. Staley // Science. – 1995. – Vol. 269. – P. 977-981.
• 60. Vaccarino F. Differential induction of immediate early genes by excitatory amino acid receptor types in primary cultures of cortical and striatal neurons / F. Vaccarino // Molec. Brain Research. – 1992. – Vol. 12, №1-3. – P. 233-241.
• 61. Wang J. Developmental loss of GABA- and glycine-induced depolarization and Ca2+ transients in embryonic rat dorsal horn neurons in culture / J. Wang // Eur. J. Neurosci. – 1994. – Vol. 6, №8. – P. 1275–1280.
• 62. Wu W. Early development of glycine and GABA-mediated synapses in spinal cord / W. Wu // J. Neurosci. – 1992. – Vol. 12, №10. – P. 3935–3945.
• 63. yuste R. Control of postsynaptic Ca2+ influx in developing neocortex by excitatory and inhibitory neurotransmitters / R. yuste, L. C. Katz // Neuron. – 1991. – Vol. 6, №3. – P. 333–344.

«Bulletin of problems biology and medicine» Issue 2 part 3 (109), 2014 year, 38-44 pages, index UDK 612. 741. 743:612. 014. 42