Impairment of gabaa receptor function byn-methyl-d-aspartate-mediated calcium influx in isolated ca1 pyramidal cells

Stelzer, Armin; Shi, Hua

doi:10.1016/0306-4522(94)90479-0

Cited by 93 publications

(45 citation statements)

References 52 publications

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“…Therefore, it is possible that enzymatic regulation of synaptic receptors in cultured neurons is different from that in acute isolated neurons in the slices. Consistent with this idea, two other previous studies show that the activated but not basal level of CaN reduces the peak amplitude of whole-cell GABA A receptor currents in acute isolated hippocampal neurons (Stelzer and Shi, 1994;Chen and Wong, 1995).…”

Section: Discussionsupporting

confidence: 74%

Interaction of Calcineurin and Type-A GABA Receptor γ₂Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

et al. 2003

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Long-term depression (LTD) is an activity-dependent weakening of synaptic efficacy at individual inhibitory synapses, a possible cellular model of learning and memory. Here, we show that the induction of LTD of inhibitory transmission recruits activated calcineurin (CaN) to dephosphorylate type-A GABA receptor (GABAARs) via the direct binding of CaN catalytic domain to the second intracellular domain of the GABAAR-γ2subunits. Prevention of the CaN–GABAAreceptor complex formation by expression of an autoinhibitory domain of CaN in the hippocampus of transgenic mice blocks the induction of LTD. Conversely, genetic expression of the CaN catalytic domain in the hippocampus depresses inhibitory synaptic responses, occluding LTD. Thus, an activity-dependent physical and functional interaction between CaN and GABAAreceptors is both necessary and sufficient for inducing LTD at CA1 individual inhibitory synapses.

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Section: Discussionsupporting

confidence: 74%

Interaction of Calcineurin and Type-A GABA Receptor γ₂Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

et al. 2003

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“…A. Dzubay, and G. L. Westbrook, unpublished observations) to ϳ50%, concurrently reducing the apparent desensitization (Jones and Westbrook, 1996). Two other studies have shown that calcineurin, activated by calcium entering through NMDA receptors, can reduce whole-cell GABA A responses (Յ 200 M GABA; 25 msec-10 sec) (Stelzer and Shi, 1994;Chen and Wong, 1995). At present, we have no satisfactory explanation for the apparent difference between those results and our own.…”

Section: The Roles Of Calcineurin and Kinases In Regulating Synaptic contrasting

confidence: 73%

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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“…GABA A receptor function is maintained by phosphorylation and disrupted by [Ca 2ϩ ] i elevation (Stelzer et al, 1988;Marchenko, 1991;Gyenes et al, 1994;Moss et al, 1995). In this respect, dephosphorylation induced by a Ca 2ϩ -dependent phosphatase may be involved in the downstream of BDNF-activated signal transduction and lead to the attenuation of GABA A response (Stelzer and Shi, 1994;Chen and Wong, 1995).…”

Section: Involvement Of Intracellular Ca 2؉ Mobilizationmentioning

confidence: 99%

Inhibition of GABA_ASynaptic Responses by Brain-Derived Neurotrophic Factor (BDNF) in Rat Hippocampus

1997

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Brain-derived neurotrophic factor (BDNF) is one of neurotrophins involved in the development and maintenance of both the peripheral nervous system and CNS. Although the expression of BDNF and its receptor TrkB still occurs in the adult stage, their physiological role in the mature CNS is not fully understood. In the present study we examined in detail the possibility that BDNF modulates synaptic neurotransmissions by using patch-clamp technique in rat hippocampal CA1 region. BDNF (20 -100 ng/ml) did not show any appreciable effect on evoked EPSCs, but it markedly reduced both evoked and spontaneous IPSCs within 5 min, and the reduction persisted while BDNF was present. BDNF also attenuated GABA A receptor-mediated response to applied GABA. However, BDNF failed to attenuate IPSCs when the postsynaptic pyramidal neuron was loaded intracellularly with 200 nM K252a, an alkaloid that inhibits the kinase activity of Trk receptor family, through the patch pipette. Intracellular application of 200 nM K252b, a weaker inhibitor of Trk-type kinase, did not affect the inhibition. The attenuating effect also was prevented by postsynaptic injection of U73122 (5 M), a broad-spectrum PLC inhibitor, and by strong chelation of intracellular Ca 2ϩ with 10 mM BAPTA. These data suggest that BDNF modulates GABA A synaptic responses by postsynaptic activation of Trk-type receptor and subsequent Ca 2ϩ mobilization in the CNS.Key words: BDNF; GABA A receptor; disinhibition; plasticity; LTP; hippocampus Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins involved in the development and maintenance of both the peripheral nervous system and CNS. During brain development neurotrophins and their receptors display distinct stage-and tissue-specific patterns of expression (Ernfors et al., 1990a;Phillips et al., 1990;Merlio et al., 1992). BDNF mRNA is observed in the embryonic stage and is still present in the postnatal and adult stages (Ernfors et al., 1990b;Maisonpierre et al., 1990; Freidman et al., 1991). In the adult stage its expression level is modulated dramatically by neuronal activity (Falkenberg et al., 1992;Patterson et al., 1992;Rocamora et al., 1992;Bengzon et al., 1993;Kokaia et al., 1993). Moreover, expression of TrkB, a functional BDNF receptor, not only increases during embryonic development but also continues to increase until several weeks after birth in the hippocampus (Masana et al., 1993;Ringstedt et al., 1993). These observations suggest that in the adult CNS dynamic change in BDNF level still can trigger neuronal plasticity via activation of TrkB. Indeed, neurotrophins are secreted by neurons in both a constitutive and an activity-dependent manner Thoenen, 1995, 1996;Griesbeck et al., 1995;Thoenen, 1995;Goodmann et al., 1996). Additionally, BDNF induces long-lasting enhancement of synaptic transmission (Kang and Schuman, 1995) and facilitates the induction of long-term potentiation (LTP) in the hippocampus (Figurov et al., 1996); however, the site and mechanism of action of BDNF remain unclear, becau...

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Impairment of gabaa receptor function byn-methyl-d-aspartate-mediated calcium influx in isolated ca1 pyramidal cells

Cited by 93 publications

References 52 publications

Interaction of Calcineurin and Type-A GABA Receptor γ₂Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

Interaction of Calcineurin and Type-A GABA Receptor γ₂Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

Shaping of IPSCs by Endogenous Calcineurin Activity

Inhibition of GABA_ASynaptic Responses by Brain-Derived Neurotrophic Factor (BDNF) in Rat Hippocampus

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Impairment of gabaa receptor function byn-methyl-d-aspartate-mediated calcium influx in isolated ca1 pyramidal cells

Cited by 93 publications

References 52 publications

Interaction of Calcineurin and Type-A GABA Receptor γ2Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

Interaction of Calcineurin and Type-A GABA Receptor γ2Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

Shaping of IPSCs by Endogenous Calcineurin Activity

Inhibition of GABAASynaptic Responses by Brain-Derived Neurotrophic Factor (BDNF) in Rat Hippocampus

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Interaction of Calcineurin and Type-A GABA Receptor γ₂Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

Interaction of Calcineurin and Type-A GABA Receptor γ₂Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

Inhibition of GABA_ASynaptic Responses by Brain-Derived Neurotrophic Factor (BDNF) in Rat Hippocampus