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GABA transient sets the susceptibility of mIPSCs to modulation by benzodiazepine receptor agonists in rat hippocampal neurons

By Jerzy W Mozrzymas, Tomasz Wójtowicz, Michał Piast, Katarzyna Lebida, Paulina Wyrembek and Katarzyna Mercik


Benzodiazepines (BDZs) are known to increase the amplitude and duration of IPSCs. Moreover, at low [GABA], BDZs strongly enhance GABAergic currents suggesting the up-regulation of agonist binding while their action on gating remains a matter of debate. In the present study we have examined the impact of flurazepam and zolpidem on mIPSCs by investigating their effects on GABAAR binding and gating and by considering dynamic conditions of synaptic receptor activation. Flurazepam and zolpidem enhanced the amplitude and prolonged decay of mIPSCs. Both compounds strongly enhanced responses to low [GABA] but, surprisingly, decreased the currents evoked by saturating or half-saturating [GABA]. Analysis of current responses to ultrafast GABA applications indicated that these compounds enhanced binding and desensitization of GABAA receptors. Flurazepam and zolpidem markedly prolonged deactivation of responses to low [GABA] but had almost no effect on deactivation at saturating or half-saturating [GABA]. Moreover, at low [GABA], flurazepam enhanced desensitization–deactivation coupling but zolpidem did not. Recordings of responses to half-saturating [GABA] applications revealed that appropriate timing of agonist exposure was sufficient to reproduce either a decrease or enhancement of currents by flurazepam or zolpidem. Recordings of currents mediated by recombinant (‘synaptic’) α1β2γ2 receptors reproduced all major findings observed for neuronal GABAARs. We conclude that an extremely brief agonist transient renders IPSCs particularly sensitive to the up-regulation of agonist binding by BDZs

Topics: Neuroscience
Publisher: Blackwell Publishing Ltd
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Provided by: PubMed Central

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  1. (2003a). Binding sites, singly bound states and conformation coupling shape GABA-evoked currents.
  2. (2003b). Modulation of GABAA receptors by hydrogen ions reveals synaptic GABA transient and a crucial role of the desensitization process. JN e u r o s ci23,
  3. (1987). Actions of benzodiazepine and β-carboline derivatives on γ-aminobutyric acid-activated Cl− channels recorded from membrane patches of neonatal rat cortical neurons in culture.
  4. (2000). Altering the concentration of GABA in the synaptic cleft potentiates miniature IPSCs in rat occipital cortex.
  5. (2004). Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics.
  6. (1994). Benzodiazepine and β-carboline regulation of single GABAA receptor channels of mouse spinal neurones in culture.
  7. (2005). Benzodiazepine modulation of partial agonist efficacy and spontaneously active GABAA receptors supports an allosteric model of modulation.
  8. Benzodiazepines act on GABAA receptors via two distinct and separable mechanisms.
  9. (1998). Binding, gating, affinity and efficacy: the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors.
  10. C h e r u b i n iE&C o n t iF(2001). Generating diversity at GABAergic synapses.
  11. (2000). Cell type- and synapse-specific variability in synaptic GABAA receptor occupancy. E u rJN e u r o s ci12,
  12. Chlorpromazine inhibits miniature GABAergic currents by reducing the binding and by increasing the unbinding rate of GABAA receptors.
  13. (2005). Classic benzodiazepines modulate the open-close equilibrium in α1β2γ2L γ-aminobutyric acid type A receptors.
  14. (1998). Contribution of subsaturating GABA concentrations to IPSCs in cultured hippocampal neurons. JN e u r o s ci18,
  15. (1995). Desensitized states prolong GABAA channel responses to brief agonist pulses.
  16. (1997). Differences in synaptic GABAA receptor number underlie variation in GABA mini amplitude.
  17. (1989). Differential regulation of γ-aminobutyric acid receptor channels by diazepam and phenobarbital.
  18. (1996). Direct evidence for diazepam modulation of GABAA receptor microscopic affinity.
  19. (2004). Dynamism of GABAA receptor activation shapes the ‘personality’ of inhibitory synapses.
  20. (1999). Effect of zolpidem on miniature IPSCs and occupancy of postsynaptic GABAA receptors in central synapses.
  21. (1995). Fast application of agonists to isolated membrane patches.
  22. (2003). Formation and plasticity of GABAergic synapses: physiological mechanisms and pathophysiological implications.
  23. (1997). Frequency-dependent actions of benzodiazepines on GABAA receptors in cultured murine cerebellar granule cells.
  24. (1999). Functional GABAA receptor heterogeneity of acutely dissociated hippocampal CA1 pyramidal cells.
  25. (2006). GABA-based therapeutic approaches: GABAA receptor subtype functions.
  26. (2003). GABAA receptor subtypes in the brain: a paradigm for CNS discovery? Drug Discov Today 8,
  27. (2005). GABAA receptor subtypes: any clues to the mechanism of benzodiazepine dependence?
  28. (1987). High-efficiency transformation of mammalian cells by plasmid DNA.
  29. (1997). Hippocampal GABAA channel conductance increased by diazepam.
  30. (1997). Immunoglobulins from motoneurone disease patients enhance glutamate release from rat hippocampal neurones in culture.
  31. (1989). Kinetic properties of the GABAA receptor main conductance state of mouse spinal cord neurones in culture.
  32. (1993). Local and diffuse synaptic actions of GABA in the hippocampus.
  33. (2002). Measuring and modeling the spatiotemporal profile of GABA at the synapse.
  34. (2006). Mechanism of action of benzodiazepines on GABAA receptors.
  35. (1998). Molecular modulation of recombinant rat α1β2γ2 GABAA receptor channels by diazepam.
  36. (2004). Presynaptic source of quantal size variability at GABAergic synapses in rat hippocampal neurons in culture. E u rJN e u r o s ci20,
  37. (2003). Synapse density regulates independence at unitary inhibitory synapses.
  38. (2007). The Authors. Journal compilation C
  39. (2007). The benzodiazepine receptor agonists affect both binding and gating of recombinant α1β2γ2 GABAA receptors.
  40. (1996). Transmitter time course in the synaptic cleft: its role in the central synaptic function.
  41. (1995). Variation in GABA mini amplitude is the consequence of variation in transmitter concentration.