The Role of Presynaptic GABAB Receptors in Stimulus-Dependent Disinhibition and the Induction of Long-Term Potentiation

  • Darrell V. Lewis
  • David D. Mott
  • H. Scott Swartzwelder
  • Cui-Wei Xie


The existence of gamma-aminobutyric acidB (GABAB) autoreceptors regulating GABA release is supported by studies using both synaptosomal preparations (Bonanno et al., 1989a,b; Anderson and Mitchell, 1985) and intact cellular systems (Waldmeier et al., 1988; Harrison et al., 1988; Harrison, 1990). The chapter by Lambert and Harrison (this volume) reviews the electrophysiological data indicating the presence of GABAB autoreceptors. The next step in unraveling the significance of these receptors is to determine their effects on the behavior of neurons in active neural circuits. In this chapter, we demonstrate how stimulus-dependent disinhibition mediated by GABAB receptors enhanced N-methyl-D-aspartate (NMDA) receptor-mediated currents, discuss the evidence that GABAB autoreceptors mediate stimulus-dependent disinhibition, and demonstrate how GABAB-mediated stimulus-dependent disinhibition facilitates long-term potentiation (LTP) and polysynaptic transmission in the hippocampal formation.


Granule Cell Dentate Gyrus Mossy Fiber Population Spike Perforant Path 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Anderson RA, Mitchell R (1985): Evidence for GABAB autoreceptors in median eminence. Eur J Pharmacol 118:355–358PubMedCrossRefGoogle Scholar
  2. Andrade R, Malenka RC, Nicoli RA (1986): A G protein couples serotonin and GABAB receptors to the same channels in hippocampus. Science 234:1261–1263PubMedCrossRefGoogle Scholar
  3. Ault B, Nadler JV (1983a): Anticonvulsant-like actions of baclofen in the rat hippocampal slice. Br J Pharmacol 78:701–708PubMedGoogle Scholar
  4. Ault B, Nadler JV (1983b): Effects of baclofen on synaptically-induced cell firing in the rat hippocampal slice. Br J Pharmacol 80:211–219PubMedGoogle Scholar
  5. Ben-Ari Y, Krnjevic K, Reinhardt W (1979): Hippocampal seizures and failure of inhibition. Can J Physiol Pharmacol 57:1462–1466CrossRefGoogle Scholar
  6. Bonanno G, Pellegrini G, Asaro D, Fontana G, Raiteri M (1989a): GABAB autoreceptors in rat cortex synaptosomes: response under different depolarizing and ionic conditions. Eur J Pharmacol 172:41–49PubMedCrossRefGoogle Scholar
  7. Bonanno G, Cavazzani P, Andriolo GC, Asaro D, Pellegrini G, Raiteri M (1989b): Release-regulating autoreceptors of the GABAB-type in human cerebral cortex. Br J Pharmacol 96:341–346PubMedGoogle Scholar
  8. Brucato F, Morrisett RA, Wilson WA, Swartzwelder HS (1992): The GABAB receptor antagonist, CGP-35348, inhibits paired pulse disinhibition in the rat dentate gyrus in vivo Brain Res 588:150–153, 1992PubMedCrossRefGoogle Scholar
  9. Buzsáki G (1986): Generation of hippocampal EEG patterns. In: The Hippocampus, Vol. 3, Isaacson RL, Pribram KH, eds. New York: Plenum PressGoogle Scholar
  10. Chen QX, Stelzer A, Kay AR, Wong RKS (1990): GABAA receptor function is regulated by phosphorylation in acutely dissociated guinea-pig hippocampal neurones. J Physiol (Lond) 420:207–221Google Scholar
  11. Connors BW, Malenka RC, Silva LR (1988): Two inhibitory postsynaptic potentials, and GABAA and GABAB receptor-mediated responses in neocortex of rat and cat. J Physiol 406:443–468PubMedGoogle Scholar
  12. Crunelli V, Leresche N (1991): A role for GABAB receptors in excitation and inhibition of thalamocortical cells. TINS 14:16–21PubMedGoogle Scholar
  13. Davies CH, Davies SN, Collingridge GL (1990): paired-pulse depression of monosynaptic GABA-mediated inhibitory postsynaptic responses in rat hippocampus. J Physiol 424:513–531PubMedGoogle Scholar
  14. Davies CH, Starkey SJ, Possa MF, Collingridge GL (1991): GABAB receptors regulate the induction of LTP. Nature 349:609–611PubMedCrossRefGoogle Scholar
  15. Deisz RA, Prince DA (1989): Frequency dependent depression of inhibition in the guinea pig neocortex in vitro by GABAB receptor feedback on GABA release. J Physiol 412:513–541PubMedGoogle Scholar
  16. Diamond DM, Dunwiddie TV, Rose GM (1988): Characteristics of hippocampal primed burst potentiation in vitro and in the awake rat. J Neurosci 8:4079–4088PubMedGoogle Scholar
  17. Dutar P, Nicoli RA (1988): Pre- and Postsynaptic GABAB receptors in the hippocampus have different pharmacological properties. Neuron 1:585–591PubMedCrossRefGoogle Scholar
  18. Fox SE, Wolfson S, Ranck JB Jr (1986): Hippocampal theta rhythm and the firing of neurons in walking and urethane anesthetized rats. Exp Brain Res 62:495–508PubMedCrossRefGoogle Scholar
  19. Greenstein YJ, Pavlides C, Winson J (1988): Long-term potentiation in the dentate gyrus is preferentially induced at theta rhythm periodicity. Brain Res 438:331–334PubMedCrossRefGoogle Scholar
  20. Harrison NL, Lange GD, Barker JL (1988): (-)Baclofen activates presynaptic GABAB receptors on GABAergic inhibitory neurons from embryonic rat hippocampus. Neurosci Lett 85:105–109PubMedCrossRefGoogle Scholar
  21. Harrison NL (1990): On the presynaptic action of baclofen at inhibitory synapses between cultured rat hippocampal neurones. J Physiol 422:433–446PubMedGoogle Scholar
  22. Herron CE, Lester RA, Coan EJ, Collingridge GL (1986): Frequency-dependent involvement of NMDA receptors in the hippocampus: a novel synaptic mechanism. Nature 322:265–268PubMedCrossRefGoogle Scholar
  23. Huguenard JR, Alger BE (1986): Whole-cell voltage-clamp study of the fading of GABA-activated currents in acutely dissociated hippocampal neurons. J Neurophysiol 56:1–18PubMedGoogle Scholar
  24. Lambert JDC, Jones RSG (1990): A reevaluation of excitatory amino acid-mediated synaptic transmission in rat dentate gyrus. J Neurophysiol 64:119–132PubMedGoogle Scholar
  25. Larson J, Lynch G (1986): Induction of synaptic potentiation in the hippocampus by patterned stimulation involves two events. Science 232:985–988PubMedCrossRefGoogle Scholar
  26. Larson J, Lynch G (1988): Role of N-methyl-D-aspartate receptors in the induction of synaptic potentiation by burst stimulation patterned after the hippocampal theta rhythm. Brain Res 441:111–118PubMedCrossRefGoogle Scholar
  27. Lewis DV, Jones LS, Mott DD (1989): Baclofen induces spontaneous, rhythmic sharp waves in the rat hippocampal slice. Exp Neurol 106:181–186PubMedCrossRefGoogle Scholar
  28. McCarren M, Alger BE (1985): Use dependent depression of IPSPs in hippocmpal cells in vitro. J Neurophysiol 53:557–571PubMedGoogle Scholar
  29. McNaughton BL (1980): Evidence for two physiologically distinct perforant pathways to the fascia dentata. Brain Res 199:1–19PubMedCrossRefGoogle Scholar
  30. Misgeld U, Klee MR, Zeise ML (1984): Differences in baclofen-sensitivity between CA3 neurons and granule cells of the guinea pig hippocampus in vitro. Neurosci Lett 47:307–311PubMedCrossRefGoogle Scholar
  31. Misgeld U, Muller W, Brunner H (1989): Effects of (-)baclofen on inhibitory neurons in the guinea pig hippocampal slice. Pflugers Arch 414:139–144PubMedCrossRefGoogle Scholar
  32. Morrisett RA, Mott DD, Lewis DV, Swartzwelder HS, Wilson WA (1991): GABAB-receptor mediated inhibition of the N-methyl-D-aspartate component of synaptic transmission in the rat hippocampus. J Neurosci 11:203–209PubMedGoogle Scholar
  33. Mott DD, Bragdon AC, Lewis DV, Wilson WA (1989): Baclofen has a proepileptic effect in the rat dentate gyrus. J Pharmacol Exp Ther 249:721–725PubMedGoogle Scholar
  34. Mott DD, Lewis DV (1990a): Fading of recurrent inhibition in the rat dentate gyrus is mediated by GABAB receptors. Soc Neurosci Abstr 16:945Google Scholar
  35. Mott DD, Lewis DV, Ferrari CM, Wilson WA, Swartzwelder HS (1990b): Baclofen facilitates the development of long term potentiation in the rat dentate gyrus. Neurosci Lett 113:222–226PubMedCrossRefGoogle Scholar
  36. Mott DD, Bragdon AC, Lewis DV (1990c): Phaclofen antagonizes post-tetanic disinhibi-tion in the rat dentate gyrus. Neurosci Lett 110:131–136PubMedCrossRefGoogle Scholar
  37. Mott DD, Lewis DV (1991): Facilitation of the induction of long-term potentiation by GABAB receptors. Science 252:17180–1720CrossRefGoogle Scholar
  38. Mott DD, Xie CW, Morrisett RA, Swartzwelder HS, Wilson WA, Lewis DV (1991): GABAB receptor-mediated paired pulse disinhibition reveals an NMDA component of the EPSP. Soc Neurosci Abstr 17:1169Google Scholar
  39. Mott DD, Xie CW, Wilson WA, Swartzwelder HS, Lewis DV (1993): GABAB autoreceptors mediate frequency dependent disinhibition and enhance signal transmission in the dentate gyrus. J Neurophysiol 69:674–691PubMedGoogle Scholar
  40. Mott DD, Xie CW, Wilson WA, Swartzwelder HS, Lewis DV (1992): Physiological significance of GABAB mediated disinhibition in the dentate gyrus. Pharmacol Comm 2:104–108Google Scholar
  41. Nathan T, Jensen MS, Lambert JDC (1990): GABAB receptors play a major role in paired-pulse facilitation in area CA1 of the rat hippocampus. Brain Res 531:55–65PubMedCrossRefGoogle Scholar
  42. Olpe HR, Karlsson G (1990): The effects of baclofen and two GABAB-receptor antagonists on long-term potentiation. Naunyn-Schmiedeberg’s Arch Pharmacol 342:194–197CrossRefGoogle Scholar
  43. Otto T, Eichenbaum H, Wiener SI, Wible CG (1991): Learning-related patterns of CA1 spike trains parallel stimulation parameters optimal for inducing hippocampal long-term potentiation. Hippocampus 1:181–192PubMedCrossRefGoogle Scholar
  44. Pacelli GJ, Su W, Kelso SR (1989): Activity-induced depression of synaptic inhibition during LTP-inducing patterned stimulation. Brain Res 486:26–32PubMedCrossRefGoogle Scholar
  45. Pavlides C, Greenstein YJ, Grudman M, Winson J (1988): Long-term potentiation in the dentate gyrus is induced preferentially on the positive phase of theta rhythm. Brain Res 439:383–387PubMedCrossRefGoogle Scholar
  46. Peet MJ, McLennan H (1986): Pre and postsynaptic actions of baclofen: blockade of the late synaptically evoked hyperpolarization of CA1 hippocampal neurones. Exp Brain Res 61:567–574PubMedCrossRefGoogle Scholar
  47. Rose G (1983): Physiological and behavioral characteristics of dentate granule cells. In: Neurobiology of the Hippocampus, Seifert W, eds. London: Academic PressGoogle Scholar
  48. Rovira C, Ben-Ari Y, Cherubini E (1984): Somatic and dendritic actions of gamma-aminobutyric acid agonists and uptake blockers in the hippocampus in vivo. Neuroscience 12:543–555PubMedCrossRefGoogle Scholar
  49. Steffensen SC, Henriksen SJ (1991): Effects of baclofen and bicuculline on inhibition in the fascia dentata and hippocampus regio superior. Brain Res 538:46–53PubMedCrossRefGoogle Scholar
  50. Thalmann RH (1988): Evidence that guanosine triphosphate (GTP)-binding proteins control a synaptic response in brain: effect of pertussis toxin and GTP-gamma-S on the late inhibitory postsynaptic potential of hippocampal CA3 neurons. J Neurophysiol 8:4589–4602Google Scholar
  51. Thompson SM, Gahwiler BH (1989a): Activity-dependent disinhibition III. Desensitiza-tion and GABAB receptor-mediated presynaptic inhibition in the hippocampus in vitro. J Neurophysiol 61:524–533PubMedGoogle Scholar
  52. Thompson SM, Gahwiler BH (1989b): Activity-dependent disinhibition. I. Repetitive stimulation reduces IPSP driving force and conductance in the hippocampus in vitro. J Neurophysiol 61:501–511PubMedGoogle Scholar
  53. Waldmeier PC, Wicki P, Feldtrauer JJ, Baumann PA (1988): Potential involvement of a baclofen-sensitive autoreceptor in the modulation of the release of endogenous GABA from rat brain slices in vitro. Naunyn-Schmiedeberg’s Arch Pharmacol 337:289–295Google Scholar
  54. Wong RKS, Watkins DJ (1982): Cellular factors influencing GABA response in hippocampal pyramidal cells. J Neurophysiol 48:938–951PubMedGoogle Scholar
  55. Xie CW, Morrisett RA, Lewis DV (1992): Mu opioid receptor-mediated modulation of synaptic currents in dentate granule cells of rat hippocampus. J Neurophysiol 68:1113–1120PubMedGoogle Scholar

Copyright information

© Birkhäuser Boston 1993

Authors and Affiliations

  • Darrell V. Lewis
  • David D. Mott
  • H. Scott Swartzwelder
  • Cui-Wei Xie

There are no affiliations available

Personalised recommendations