GABAB autoreceptors regulate the induction of LTP

Davies, Ceri H.; Starkey, Sarah J.; Pozza, Mario F.; Collingridge, Graham L.

doi:10.1038/349609a0

Cited by 578 publications

(342 citation statements)

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“…Indeed, exogenous BDNF promotes the induction of LTP in the young hippocampus; in turn, endogenous BDNF is suggested to be involved in the triggering mechanism of LTP in the adult (Figurov et al, 1996). Disinhibition induced by BDNF will participate in the induction of LTP, because elimination of GABAergic hyperpolarizing influence relieves voltage-dependent Mg 2ϩ block of NMDA receptor-channel and facilitates the induction of LTP (Davies et al, 1991;Mott and Lewis, 1991). This also is supported by the results of mutant mice lacking BDNF (Korte et al, 1995), which showed significantly reduced LTP in the hippocampus.…”

Section: Inhibition Of Gaba a Receptor-mediated Ipscs By Bdnfmentioning

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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Section: Inhibition Of Gaba a Receptor-mediated Ipscs By Bdnfmentioning

confidence: 99%

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

1997

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“…The effects of GABA B R activation on the network are dominated by inhibition leading to an overall dampened population activity. However, if GABAergic interneurons are effected dominantly, as observed for example, during high-frequency stimulation, GABA B R activation can produce disinhibition in principal cells (12,13). Accordingly, the role of GABA B Rs in epilepsy and seizure generation remains ambiguous.…”

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confidence: 99%

GABA _B autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice

Dugladze

Maziashvili

Börgers

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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GABA B receptors (GABA B Rs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABA B R agonist baclofen can also promote excitability and seizure generation in human patients and animals models. Here we show that baclofen has concentration-dependent effects on the hippocampal network in a mouse model of mesial temporal lobe epilepsy. Application of baclofen at a high dose (10 mg/kg i.p.) reduced the power of γ oscillations and the frequency of pathological discharges in the Cornu Ammonis area 3 (CA3) area of freely moving epileptic mice. Unexpectedly, at a lower dose (1 mg/kg), baclofen markedly increased γ activity accompanied by a higher incidence of pathological discharges. Intracellular recordings from CA3 pyramidal cells in vitro further revealed that, although at a high concentration (10 μM), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 μM), the drug had divergent effects, producing depolarization and an increase in firing frequency in epileptic but not control mice. These excitatory effects were mediated by the selective muting of inhibitory cholecystokinin-positive basket cells (CCK + BCs), through enhanced inhibition of GABA release via presynaptic GABA B Rs. We conclude that cell type-specific up-regulation of GABA B R-mediated autoinhibition in CCK + BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice.presynaptic inhibition | mTLE model | patch clamp N euronal activity in the hippocampus shows oscillations in behavior-relevant frequency ranges including γ frequencies (30-80 Hz) (1). γ activity is prominent in the aroused brain and has been implicated in higher-level brain functions, such as sensory binding, perception (2), and storage and recall of information (3, 4). At the same time, γ frequency oscillations are also prevalent in epileptic patients and are most often observed at seizure onset during in depth EEG recordings (5). The GABAergic system plays a pivotal role in the generation of γ oscillations (6-8). However, it remains to be resolved how distinct GABAergic receptor subtypes, in particular GABA B receptors (GABA B Rs), contribute to the generation and modulation of pathological network oscillatory activity.GABA B Rs mediate slow inhibitory effects and control synaptic transmission and the excitability of neurons in cortical networks. GABA B Rs are expressed both postsynaptically in somatodendritic compartments and presynaptically in axon terminals, in excitatory principal cell and inhibitory interneurons (9-11). The effects of GABA B R activation on the network are dominated by inhibition leading to an overall dampened population activity. However, if GABAergic interneurons are effected dominantly, as observed for example, during high-frequency stimulation, GABA B R activation can produce disinhibition in principal cells (12,13). Accordingly, the role of GABA B Rs in epilepsy and seizure generation remains ambiguous. GABA B Rs ...

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“…As such, the question still remains as to whether pharmacologically distinguishable GABA B receptors are activated by synaptically released GABA. The answer to this question is important as it will provide a better understanding of the normal physiological and pathological roles that GABA B receptors play in vivo, most notably in terms of their e ects on mnemonic processing (Olpe & Karlsson, 1990;Davies et al, 1991;Mott & Lewis, 1991;Mondadori et al, 1993;Olpe et al, 1993b) and absence epilepsy (Liu et al, 1992;Hosford et al, 1992). Ultimately, this may lead to the development of a new generation of compounds that through targeting of speci®c GABA B receptor populations may be more e cacious in treating speci®c disease states.…”

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confidence: 99%

Comparison of antagonist potencies at pre‐ and post‐synaptic GABA_B receptors at inhibitory synapses in the CA1 region of the rat hippocampus

Pozza

Manuel

Steinmann

et al. 1999

British J Pharmacology

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1 Synaptic activation of g-aminobutyric acid (GABA) B receptors at GABA synapses causes (a) postsynaptic hyperpolarization mediating a slow inhibitory postsynaptic potential/current (IPSP/C) and (b) presynaptic inhibition of GABA release which depresses IPSPs and leads to paired-pulse widening of excitatory postsynaptic potentials (EPSPs). To address whether these e ects are mediated by pharmacologically identical receptors the e ects of six GABA B receptor antagonists of widely ranging potencies were tested against each response. 2 Monosynaptic IPSP B s were recorded in the presence of GABA A , AMPA/kainate and NMDA receptor antagonists. All GABA B receptor antagonists tested depressed the IPSP B with an IC 50 based rank order of potency of CGP556795CGP56433=CGP55845A=CGP524324CGP511764 CGP36742. 3 Paired-pulse EPSP widening was recorded as an index of paired-pulse depression of GABAmediated IPSP/Cs. A similar rank order of potency of antagonism of paired-pulse widening was observed to that for IPSP B inhibition. 4 Comparison of the IC 50 values for IPSP B inhibition and paired-pulse EPSP widening revealed a close correlation between the two e ects in that their IC 50 s lay within the 95% con®dence limits of a correlation line that described IC 50 values for inhibition of paired-pulse EPSP widening that were 7.3 times higher than those for IPSP B inhibition. 5 Using the compounds tested here it is not possible to assign di erent subtypes of GABA B receptor to pre-and post-synaptic loci at GABAergic synapses. However, 5 ± 10 fold higher concentrations of antagonist are required to block presynaptic as opposed to postsynaptic receptors when these are activated by synaptically released GABA.

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GABAB autoreceptors regulate the induction of LTP

Cited by 578 publications

References 23 publications

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

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

GABA _B autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice

Comparison of antagonist potencies at pre‐ and post‐synaptic GABA_B receptors at inhibitory synapses in the CA1 region of the rat hippocampus

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GABAB autoreceptors regulate the induction of LTP

Cited by 578 publications

References 23 publications

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

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

GABA B autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice

Comparison of antagonist potencies at pre‐ and post‐synaptic GABAB receptors at inhibitory synapses in the CA1 region of the rat hippocampus

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

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

GABA _B autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice

Comparison of antagonist potencies at pre‐ and post‐synaptic GABA_B receptors at inhibitory synapses in the CA1 region of the rat hippocampus