Temporally distinct mechanisms of use-dependent depression at inhibitory synapses in the rat hippocampus in vitro

Nevin A Lambert, W. A. Wilson

Research output: Contribution to journalArticle

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Abstract

1. γ-aminobuturic acid-B (GABA(B)) autoreceptor-dependent and - independent components of paired-pulse depression (PPD) at inhibitory synapses in area CA3 of the rat hippocampus were studied using whole-cell recording techniques. Inhibitory fibers were activated directly in the presence of the ionotropic glutamate receptor antagonists 6,7- dinitroquinoxaline-2,3-dione (20 μM) and D-2-amino-5-phosphonovalerate (20 μM). 2. When pairs of monosynaptic inhibitory postsynaptic currents (eIPSCs) were evoked with an interstimulus interval of 200 ms, the amplitude of the second response (eIPSC2) was depressed when compared with the first (eIPSC1). The GABA(B) receptor agonist baclofen (10 μM) depressed both responses, but eIPSC1 was depressed more than eIPSC2, resulting in PPD that was comparatively smaller. Addition of the GABA(B) receptor antagonist CGP 55845A (1 μM) completely reversed depression of eIPSC1 by baclofen and increased the amplitude of eIPSC2 above the control value, such that PPD in the combination of baclofen and CGP 55845 A was equivalent to that in baclofen alone. The ratio eIPSC2/eIPSC1 was 0.64 under control conditions, 0.77 in the presence of baclofen, and 0.79 in the presence of baclofen and CGP 55845A. These results demonstrate the existence of two components of PPD at inhibitory synapses, one that depends on activation of GABA(B) autoreceptors (GABA(B) receptor-dependent PPD) and one that does not (GABA(B) receptor-independent PPD). 3. When the number of inhibitory fibers activated was lowered by decreasing the stimulus intensity, eIPSC2/eIPSC1 was 0.76 under control conditions, 0.75 in the presence of baclofen, and 0.76 in the presence of baclofen and CGP 55845A. These results indicate that GABA(B) receptor-dependent PPD requires activation of several presynaptic inhibitory neurons, whereas GABA(B) receptor-independent PPD does not. 4. The timecourses of the GABA(B)-dependent and -independent components of PPD were compared by varying the interstimulus interval in the absence and presence of CGP 55845A. GABA(B)-dependent PPD was maximal at an interstimulus interval of 100 ms and was undetectable at 1 s. In contrast, GABA(B)-independent PPD was maximal at 5 ms and 1 s, was slightly less pronounced at intermediate intervals (50-200 ms), and was present at intervals as long as 5 s. 5. GABA(B)-independent PPD was not blocked by antagonists at opioid receptors (10 μM naloxone) or muscarinic acetylcholine receptors (10 μM atropine). GABA(B)-independent PPD could not be accounted for by a decrease in driving force because of Cl- redistribution. 6. When the probability of neurotransmitter release was lowered by increasing the extracellular concentration of Mg2+ from 1 mM to 5-8 mM, GABA(B)-independent PPD at intermediate interstimulus intervals (20-200 ms) was diminished or reversed into paired-pulse facilitation (PPF). GABA(B)-independent PPD at interstimulus intervals of 500 ms or greater was not changed by increasing Mg2+. 7. Postsynaptic currents could be elicited in an all-or-none manner at a threshold intensity when the stimulus intensity was increased slowly from 1 μA to ~20 μA. These minimal evoked inhibitory postsynaptic currents (meIPSCs) presumably resulted from the activation of single inhibitory fibers. GABA(B)-independent PPD of meIPSCs was similar to that of eIPSCs; meIPSC2/meIPSC1 was 0.73 at an interstimulus interval of 100 ms. PPD was observed of meIPSCs that were unaffected by baclofen or CGP 55845A. GABA(B) independent PPD did not change the rise or decay kinetics of meIPSCs, but was accompanied by an increase in the variability of meIPSC2. These results indicate that GABA(B)-independent PPD occurs at synapses made by single inhibitory neurons. 8. These results demonstrate two components of PPD at hippocampal inhibitory synapses. One component is mediated by activation of GABA(B) autoreceptors, as described previously, and is present for <1 s. The second component does not depend on activation of GABA(B) receptors and is present for several seconds. GABA(B) receptor-dependent PPD requires activation of several presynaptic inhibitory neurons, whereas GABA(B) receptor-independent PPD occurs at synapses made by single inhibitory neurons. GABA(B)-independent PPD appears to be similar to depression observed at several other central and peripheral synapses. Both components of PPD coexist with PPF, which can be revealed by lowering the probability of release.

Original languageEnglish (US)
Pages (from-to)121-130
Number of pages10
JournalJournal of Neurophysiology
Volume72
Issue number1
DOIs
StatePublished - Jan 1 1994
Externally publishedYes

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CGP 55845A
Synapses
gamma-Aminobutyric Acid
Hippocampus
Baclofen
GABA-B Receptors
Inhibitory Postsynaptic Potentials
Autoreceptors
Neurons
In Vitro Techniques
GABA-B Receptor Antagonists
GABA-B Receptor Agonists
2-Amino-5-phosphonovalerate
Ionotropic Glutamate Receptors
Excitatory Amino Acid Antagonists
Synaptic Potentials
Narcotic Antagonists
Patch-Clamp Techniques
Muscarinic Receptors
Naloxone

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology

Cite this

Temporally distinct mechanisms of use-dependent depression at inhibitory synapses in the rat hippocampus in vitro. / Lambert, Nevin A; Wilson, W. A.

In: Journal of Neurophysiology, Vol. 72, No. 1, 01.01.1994, p. 121-130.

Research output: Contribution to journalArticle

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N2 - 1. γ-aminobuturic acid-B (GABA(B)) autoreceptor-dependent and - independent components of paired-pulse depression (PPD) at inhibitory synapses in area CA3 of the rat hippocampus were studied using whole-cell recording techniques. Inhibitory fibers were activated directly in the presence of the ionotropic glutamate receptor antagonists 6,7- dinitroquinoxaline-2,3-dione (20 μM) and D-2-amino-5-phosphonovalerate (20 μM). 2. When pairs of monosynaptic inhibitory postsynaptic currents (eIPSCs) were evoked with an interstimulus interval of 200 ms, the amplitude of the second response (eIPSC2) was depressed when compared with the first (eIPSC1). The GABA(B) receptor agonist baclofen (10 μM) depressed both responses, but eIPSC1 was depressed more than eIPSC2, resulting in PPD that was comparatively smaller. Addition of the GABA(B) receptor antagonist CGP 55845A (1 μM) completely reversed depression of eIPSC1 by baclofen and increased the amplitude of eIPSC2 above the control value, such that PPD in the combination of baclofen and CGP 55845 A was equivalent to that in baclofen alone. The ratio eIPSC2/eIPSC1 was 0.64 under control conditions, 0.77 in the presence of baclofen, and 0.79 in the presence of baclofen and CGP 55845A. These results demonstrate the existence of two components of PPD at inhibitory synapses, one that depends on activation of GABA(B) autoreceptors (GABA(B) receptor-dependent PPD) and one that does not (GABA(B) receptor-independent PPD). 3. When the number of inhibitory fibers activated was lowered by decreasing the stimulus intensity, eIPSC2/eIPSC1 was 0.76 under control conditions, 0.75 in the presence of baclofen, and 0.76 in the presence of baclofen and CGP 55845A. These results indicate that GABA(B) receptor-dependent PPD requires activation of several presynaptic inhibitory neurons, whereas GABA(B) receptor-independent PPD does not. 4. The timecourses of the GABA(B)-dependent and -independent components of PPD were compared by varying the interstimulus interval in the absence and presence of CGP 55845A. GABA(B)-dependent PPD was maximal at an interstimulus interval of 100 ms and was undetectable at 1 s. In contrast, GABA(B)-independent PPD was maximal at 5 ms and 1 s, was slightly less pronounced at intermediate intervals (50-200 ms), and was present at intervals as long as 5 s. 5. GABA(B)-independent PPD was not blocked by antagonists at opioid receptors (10 μM naloxone) or muscarinic acetylcholine receptors (10 μM atropine). GABA(B)-independent PPD could not be accounted for by a decrease in driving force because of Cl- redistribution. 6. When the probability of neurotransmitter release was lowered by increasing the extracellular concentration of Mg2+ from 1 mM to 5-8 mM, GABA(B)-independent PPD at intermediate interstimulus intervals (20-200 ms) was diminished or reversed into paired-pulse facilitation (PPF). GABA(B)-independent PPD at interstimulus intervals of 500 ms or greater was not changed by increasing Mg2+. 7. Postsynaptic currents could be elicited in an all-or-none manner at a threshold intensity when the stimulus intensity was increased slowly from 1 μA to ~20 μA. These minimal evoked inhibitory postsynaptic currents (meIPSCs) presumably resulted from the activation of single inhibitory fibers. GABA(B)-independent PPD of meIPSCs was similar to that of eIPSCs; meIPSC2/meIPSC1 was 0.73 at an interstimulus interval of 100 ms. PPD was observed of meIPSCs that were unaffected by baclofen or CGP 55845A. GABA(B) independent PPD did not change the rise or decay kinetics of meIPSCs, but was accompanied by an increase in the variability of meIPSC2. These results indicate that GABA(B)-independent PPD occurs at synapses made by single inhibitory neurons. 8. These results demonstrate two components of PPD at hippocampal inhibitory synapses. One component is mediated by activation of GABA(B) autoreceptors, as described previously, and is present for <1 s. The second component does not depend on activation of GABA(B) receptors and is present for several seconds. GABA(B) receptor-dependent PPD requires activation of several presynaptic inhibitory neurons, whereas GABA(B) receptor-independent PPD occurs at synapses made by single inhibitory neurons. GABA(B)-independent PPD appears to be similar to depression observed at several other central and peripheral synapses. Both components of PPD coexist with PPF, which can be revealed by lowering the probability of release.

AB - 1. γ-aminobuturic acid-B (GABA(B)) autoreceptor-dependent and - independent components of paired-pulse depression (PPD) at inhibitory synapses in area CA3 of the rat hippocampus were studied using whole-cell recording techniques. Inhibitory fibers were activated directly in the presence of the ionotropic glutamate receptor antagonists 6,7- dinitroquinoxaline-2,3-dione (20 μM) and D-2-amino-5-phosphonovalerate (20 μM). 2. When pairs of monosynaptic inhibitory postsynaptic currents (eIPSCs) were evoked with an interstimulus interval of 200 ms, the amplitude of the second response (eIPSC2) was depressed when compared with the first (eIPSC1). The GABA(B) receptor agonist baclofen (10 μM) depressed both responses, but eIPSC1 was depressed more than eIPSC2, resulting in PPD that was comparatively smaller. Addition of the GABA(B) receptor antagonist CGP 55845A (1 μM) completely reversed depression of eIPSC1 by baclofen and increased the amplitude of eIPSC2 above the control value, such that PPD in the combination of baclofen and CGP 55845 A was equivalent to that in baclofen alone. The ratio eIPSC2/eIPSC1 was 0.64 under control conditions, 0.77 in the presence of baclofen, and 0.79 in the presence of baclofen and CGP 55845A. These results demonstrate the existence of two components of PPD at inhibitory synapses, one that depends on activation of GABA(B) autoreceptors (GABA(B) receptor-dependent PPD) and one that does not (GABA(B) receptor-independent PPD). 3. When the number of inhibitory fibers activated was lowered by decreasing the stimulus intensity, eIPSC2/eIPSC1 was 0.76 under control conditions, 0.75 in the presence of baclofen, and 0.76 in the presence of baclofen and CGP 55845A. These results indicate that GABA(B) receptor-dependent PPD requires activation of several presynaptic inhibitory neurons, whereas GABA(B) receptor-independent PPD does not. 4. The timecourses of the GABA(B)-dependent and -independent components of PPD were compared by varying the interstimulus interval in the absence and presence of CGP 55845A. GABA(B)-dependent PPD was maximal at an interstimulus interval of 100 ms and was undetectable at 1 s. In contrast, GABA(B)-independent PPD was maximal at 5 ms and 1 s, was slightly less pronounced at intermediate intervals (50-200 ms), and was present at intervals as long as 5 s. 5. GABA(B)-independent PPD was not blocked by antagonists at opioid receptors (10 μM naloxone) or muscarinic acetylcholine receptors (10 μM atropine). GABA(B)-independent PPD could not be accounted for by a decrease in driving force because of Cl- redistribution. 6. When the probability of neurotransmitter release was lowered by increasing the extracellular concentration of Mg2+ from 1 mM to 5-8 mM, GABA(B)-independent PPD at intermediate interstimulus intervals (20-200 ms) was diminished or reversed into paired-pulse facilitation (PPF). GABA(B)-independent PPD at interstimulus intervals of 500 ms or greater was not changed by increasing Mg2+. 7. Postsynaptic currents could be elicited in an all-or-none manner at a threshold intensity when the stimulus intensity was increased slowly from 1 μA to ~20 μA. These minimal evoked inhibitory postsynaptic currents (meIPSCs) presumably resulted from the activation of single inhibitory fibers. GABA(B)-independent PPD of meIPSCs was similar to that of eIPSCs; meIPSC2/meIPSC1 was 0.73 at an interstimulus interval of 100 ms. PPD was observed of meIPSCs that were unaffected by baclofen or CGP 55845A. GABA(B) independent PPD did not change the rise or decay kinetics of meIPSCs, but was accompanied by an increase in the variability of meIPSC2. These results indicate that GABA(B)-independent PPD occurs at synapses made by single inhibitory neurons. 8. These results demonstrate two components of PPD at hippocampal inhibitory synapses. One component is mediated by activation of GABA(B) autoreceptors, as described previously, and is present for <1 s. The second component does not depend on activation of GABA(B) receptors and is present for several seconds. GABA(B) receptor-dependent PPD requires activation of several presynaptic inhibitory neurons, whereas GABA(B) receptor-independent PPD occurs at synapses made by single inhibitory neurons. GABA(B)-independent PPD appears to be similar to depression observed at several other central and peripheral synapses. Both components of PPD coexist with PPF, which can be revealed by lowering the probability of release.

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