Synaptic Transmission in Hippocampal Neurons: Numerical Reconstruction of Quantal IPSCs

Büsch, Christopher; Sakmann, Bert

doi:10.1101/sqb.1990.055.01.009

Cited by 80 publications

(38 citation statements)

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“…Assuming free diffusion and small leakage, however, we can state that the maximum effective GABA concentration in vesicles is ϳ100 mM; above this, either the release mechanism or postsynaptic GABA A receptors are saturated. This supports modeling studies that estimate the intravesicular GABA concentration to be 80 -100 mM (Busch and Sakmann, 1990;Axmacher et al, 2004).…”

Section: Discussionsupporting

confidence: 77%

Presynaptically Silent GABA Synapses in Hippocampus

Bekkers

2005

J. Neurosci.

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Mammalian central synapses commonly specialize in one fast neurotransmitter, matching the content of their presynaptic vesicles with the appropriate receptors in their postsynaptic membrane. Here, I show that hippocampal cultures contain autaptic glutamatergic synapses that contravene this rule: in addition to postsynaptic glutamate receptors, they also express clusters of functional postsynaptic GABA A receptors yet lack presynaptic GABA. Hence, these synapses are presynaptically silent with respect to GABA. They can be unsilenced by loading GABA into presynaptic vesicles by endocytosis, after which a postload IPSC appears. This IPSC is similar to native IPSCs recorded from GABAergic interneurons in the same cultures. Thus, these "mistargeted" GABA A receptors, which apparently lack a signal that confers synaptic specificity, function almost normally. After GABA loading, glutamatergic miniature postsynaptic currents acquire a slow tail that is mediated by GABA A receptors, showing that synaptic vesicles can accommodate both the usual concentration of native glutamate and a saturating concentration of loaded GABA. After brief Ca 2ϩ -dependent exocytosis, endocytosis of GABA can proceed in low-Ca 2ϩ external solution. The amplitude of the postload IPSC declines exponentially with repetitive stimulation as the endocytosed GABA passes through the presynaptic vesicle cycle and is depleted. Hence, by using GABA as an exogenous but physiological tracer, the properties of these presynaptically silent synapses can provide novel insights into the content and cycling of vesicles in presynaptic terminals.

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Section: Discussionsupporting

confidence: 77%

Presynaptically Silent GABA Synapses in Hippocampus

Bekkers

2005

J. Neurosci.

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“…The GABA A receptor channels are thought to have more than one agonist binding site (Macdonald et al, 1989), and conducting states of multiliganded receptors could generate different kinetics from those of monoliganded receptors (Macdonald et al, 1989;Busch and Sakmann, 1990;Jones and Westbrook, 1995). We addressed this issue by comparing the decay time course of conventional and nucleated patch responses generated by a 1 msec pulse of GABA at a range of different concentrations (10 Figure 2.…”

Section: Relation Between the Decay Time Course Of Patch Currents Andmentioning

confidence: 99%

Properties of GABA_AReceptors Underlying Inhibitory Synaptic Currents in Neocortical Pyramidal Neurons

Galarreta

Hestrin

1997

J. Neurosci.

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Rapid applications of GABA (from 10 M to 10 mM) to outsideout patches were used to study the role that the kinetic properties of GABA A receptors play in determining the time course of IPSCs in neocortical pyramidal neurons. Currents induced by rapid applications of brief (1 msec) pulses of GABA (1 mM) showed a biexponential decay phase that seems to involve the entry of GABA A receptors into desensitized states. This conclusion is based on the similar fast decay kinetics of the response to brief and prolonged pulses of GABA and on the correlation between the degree of paired-pulse depression and the decay rate of the currents induced by brief pulses.Under nonequilibrium conditions we found that the concentration-response curve of pyramidal GABA A receptors has an EC 50 of 185 M (GABA pulse of 1 msec). The decay time course of the patch currents in response to brief applications of GABA was insensitive to agonist concentrations at the range from 50 M to 10 mM. Faster decay rates were observed only in response to pulses of 10 M GABA. These data are compatible with the suggestion that briefer openings derive from a monoliganded state and that these are negligible when receptor activation is Ͼ2%. Assuming that GABA transients at neocortical synapses are fast, a several millimolar GABA concentration would be needed to saturate the postsynaptic GABA A receptors.

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“…At synapses, receptors are activated by a brief, nonequilibrium exposure to a high concentration of GABA (Busch and Sakmann, 1990;Maconochie et al, 1994;Jones and Westbrook, 1995). The I PSC duration is thus primarily determined by the gating and unbinding kinetics of postsynaptic GABA A chloride channels (Maconochie et al, 1994;Jones and Westbrook, 1995).…”

Section: Abstract: Gaba a Receptor; Synapse; Phosphorylation; Modulamentioning

confidence: 99%

“…Thus, if phosphorylation affects a particular kinetic transition, the effect observed will depend strongly on whether that transition is emphasized or masked by the experimental conditions. Recent estimates suggest that the GABA concentration in the synapse reaches several hundred micromolar at its peak and decays within milliseconds (Busch and Sakmann, 1990;Maconochie et al, 1994;Jones and Westbrook, 1995). Synaptic stimulation is thus a useful "method" for producing GABA applications with a relatively stereotyped concentration and time course (for another opinion, see Frerking et al, 1995;Frerking and Wilson, 1996).…”

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confidence: 99%

Shaping of IPSCs by Endogenous Calcineurin Activity

1997

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Synaptic inhibition, mediated by GABA A receptors, regulates neuronal firing, influences coincidence detection (Kö nig et al., 1996), and can synchronize the output of neural circuits (Cobb et al., 1995). Although GABA A receptors can be modulated by phosphorylation, few studies have directly addressed the role of such modulation at synapses, where the nonequilibrium conditions of receptor activation are quite different from those often used to study GABA A receptors in vitro. Here we promoted endogenous phosphorylation by inhibiting specific phosphatases in rat hippocampal neurons and compared the effects on IPSCs with GABA A channel responses in outside-out patches. Brief and saturating GABA pulses (5 msec; 10 mM) activated patch currents resembling the IPSC. Inhibition of calcineurin (protein phosphatase 2B), but not phosphatases 1 or 2A, produced a similar shortening of IPSC and patch responses, as did nonspecific inhibition of dephosphorylation using ATP␥S or high concentrations of intracellular phosphate. Calcineurin inhibition increased the microscopic ligand unbinding rate, which was measured using the competitive antagonist 2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl)pyridazinium bromide, suggesting that the IPSC shortening was partly caused by destabilization of the ligand binding site. Calcineurin inhibition also increased the rate and extent of macroscopic receptor desensitization. These results show that endogenous regulation by kinases and calcineurin can produce substantial changes in the IPSC duration by altering the unbinding and gating kinetics of the GABA A receptor. Dynamic regulation of synaptic inhibition may thus allow for the tuning of circuit behavior at the level of individual inhibitory synapses.

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Synaptic Transmission in Hippocampal Neurons: Numerical Reconstruction of Quantal IPSCs

Cited by 80 publications

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Presynaptically Silent GABA Synapses in Hippocampus

Presynaptically Silent GABA Synapses in Hippocampus

Properties of GABA_AReceptors Underlying Inhibitory Synaptic Currents in Neocortical Pyramidal Neurons

Shaping of IPSCs by Endogenous Calcineurin Activity

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Synaptic Transmission in Hippocampal Neurons: Numerical Reconstruction of Quantal IPSCs

Cited by 80 publications

References 0 publications

Presynaptically Silent GABA Synapses in Hippocampus

Presynaptically Silent GABA Synapses in Hippocampus

Properties of GABAAReceptors Underlying Inhibitory Synaptic Currents in Neocortical Pyramidal Neurons

Shaping of IPSCs by Endogenous Calcineurin Activity

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Properties of GABA_AReceptors Underlying Inhibitory Synaptic Currents in Neocortical Pyramidal Neurons