Factors contributing to the decay of the stimulus-evoked IPSC in rat hippocampal CA1 neurons.
1. Monosynaptic gamma-aminobutyric acid-A (GABAA)-mediated inhibitory postsynaptic currents (IPSCs) were evoked in CA1 pyramidal neurons in the hippocampal slice preparation by direct stimulation of the interneurons in the presence of glutamatergic blockers and intracellular QX-314 to block GABAB-mediated postsynaptic inhibition. 2. Paired-pulse stimulation was used to activate presynaptic GABAB autoreceptors and thereby reduce the amount of transmitter release. This caused paired-pulse depression, persisting for > 3 s, and maximal at interpulse intervals between 100 and 250 ms where peak current (Ipeak) was decreased by 29.7% and decay time (t1/2) was decreased by 44.7%. There was clear correlation between changes in Ipeak and t1/2 at all interpulse intervals. 3. With paired-pulse stimulation, the decay of the second IPSC in most cells (12/18) could be resolved into two components, Ifast and Islow, each decaying monoexponentially with tau fast = 14.10 ms and tau slow = 58.87 ms. The faster decay during paired-pulse depression was predominantly caused by a larger Ifast fraction, which accounted for 27.5% of Ipeak in a single control IPSC and 79.3% at an interpulse interval of 250 ms. 4. Reducing the probability for transmitter release at all active sites by reducing [Ca2+]o from 2 mM to 1 mM decreased Ipeak by 49.7%, reduced paired-pulse depression, and partly mimicked the changes in decay kinetics seen after activation of presynaptic GABAB receptors. Lowering the stimulating intensity to 10% of the maximal value decreased Ipeak by 73.8%, but hardly affected the decay of the IPSC and the paired-pulse depression. 5. Application of the selective blocker of GABA uptake, tiagabine (20-50 microM), increased t1/2 of a single IPSC by 114% without affecting Ipeak. The increase was caused solely by an increase in tau slow of 141%. On the other hand, the benzodiazepine agonist midazolam (2 microM), selectively increased tau fast. It therefore is suggested that tau fast reflects the kinetics of the GABAA receptor/ionophore complex and tau slow the efficiency of the GABA uptake system. 6. The findings show that GABA activates postsynaptic receptors throughout the tail of a single IPSC. This could be caused by reactivation of synaptic receptors or activation of extrasynaptic receptors. The decay therefore is limited mainly by the efficiency of the uptake system. An IPSC that is maximally depressed by paired-pulse stimulation is mediated primarily by a single activation of synaptic receptors, and the decay is limited mainly by the kinetics of the GABAA receptor/ionophore complex.(ABSTRACT TRUNCATED AT 400 WORDS)
Roepstorff
A
A
PharmaBiotec Research Centre, Institute of Physiology, University of Aarhus, Denmark.
Lambert
J D
JD
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000502:physiology; D058788:GABA-B Receptor Antagonists; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008839:Microelectrodes; D008874:Midazolam / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology; D017966:Pyramidal Cells / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000187:drug effects; D013569:Synapses / Q000502:physiology*; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D058788:GABA-B Receptor Antagonists; D009557:Nipecotic Acids; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D008874:Midazolam; D002118:Calcium; D000078308:Tiagabine