Multiple and Plastic Receptors Mediate Tonic GABA<sub>A</sub>Receptor Currents in the Hippocampus

Scimemi, Annalisa; Semyanov, Alexey; Sperk, Günther; Kullmann, Dimitri M.; Walker, Matthew C.

doi:10.1523/jneurosci.2520-05.2005

Cited by 211 publications

(228 citation statements)

References 49 publications

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“…Tonic GABA inhibition was determined as the steady-state inward current that was sensitive to the GABA A R antagonist bicuculline (50 mM). Consistent with previous reports, 22,23 we observed only a small tonic GABA current in CA1 pyramidal cells from wt mice (11.3 ± 1.1 pA, n = 10). In striking contrast, CA1 pyramidal cells from two independent lines of dnActRIB mice (L1 and L3), 7 displayed significantly stronger tonic GABA inhibition (L1 25.5±3.3 pA, n = 6, P = 0.006; L3 27.4±2.3 pA, n = 5, P = 0.001; Figures 3a and b; left columns).…”

Section: Dnactrib Mice Display a Low-anxiety Phenotype And Respond Posupporting

confidence: 93%

“…Recent evidence from CA1 pyramidal cells suggests indeed that, besides a5GABA A Rs, 30,38 a4GABA A Rs (combined with d-subunit) participate in tonic inhibition. 22 Since a4GABA A Rs are benzodiazepine-insensitive, their apparent upregulation in tg CA1 pyramidal cells (at the expense of benzodiazepine-sensitive GABA A Rs) could be in part responsible for the reduced diazepam sensitivity in tg CA1 pyramidal cells. In addition, the loss of activin signaling might possibly affect the phosphorylation status of GABA A Rs, thereby influencing their allosteric modulation by benzodiazepines.…”

Section: Discussionmentioning

confidence: 99%

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Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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Activin, a member of the transforming growth factor-b superfamily, affords neuroprotection in acute brain injury, but its physiological functions in normal adult brain are largely unknown. Using transgenic (tg) mice expressing a dominant-negative activin receptor mutant under the control of the CaMKIIa promoter in forebrain neurons, we identified activin as a key regulator of c-aminobutyric acid (GABA)ergic synapses and anxiety-like behavior. In the open field, wildtype (wt) and tg mice did not differ in spontaneous locomotion and exploration behavior. However, tg mice visited inner fields significantly more often than wt mice. In the light-dark exploration test, tg mice made more exits, spent significantly more time on a well-lit elevated bar and went farther away from the dark box as compared to wt mice. In addition, the anxiolytic effect of diazepam was abrogated in tg mice. Thus the disruption of activin receptor signaling produced a low-anxiety phenotype that failed to respond to benzodiazepines. In whole-cell recordings from hippocampal pyramidal cells, enhanced spontaneous GABA release, increased GABA tonus, reduced benzodiazepine sensitivity and augmented GABA B receptor function emerged as likely substrates of the low-anxiety phenotype. These data provide strong evidence that activin influences pre-and postsynaptic components of GABAergic synapses in a highly synergistic fashion. Given the crucial role of GABAergic neurotransmission in emotional states, anxiety and depression, dysfunctions of activin receptor signaling could be involved in affective disorders: and drugs affecting this pathway might show promise for psychopharmacological treatment.

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Section: Dnactrib Mice Display a Low-anxiety Phenotype And Respond Posupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Zheng

Adelsberger²,

et al. 2008

Mol Psychiatry

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“…No effect of genotype was observed on mIPSC amplitude, rise time or decay time although a trend for a decrease in frequency was observed (Figure 3). Further, no effect of genotype was observed on the extent of tonic GABAergic activation [57] measured in the presence of the GABA A receptor antagonist BMR (18.4 ± 14.0 vs. 15.8 ± 10.9 pA, p>0.05). Additionally, there was no effect of genotype on the tonic response to KA (3 μM) in the presence of TTX (PTGS-2 +/+ = 35.2 ± 14.1 pA vs. PTGS-2 -/-= 33.8 ± 15.0 pA, p > 0.05), suggesting the electrophysiological characteristics of the KA receptor are not altered by PTGS deletion.…”

Section: Whole Cell Recordings From Ca1 Pyramidal Neurons From Ptgs-2mentioning

confidence: 83%

Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice

Toscano

Ueda

Tomita

et al. 2008

Brain Research Bulletin

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Excitotoxicity involves over activation of brain excitatory glutamate receptors and has been implicated in neurological, neurodegenerative and neuropsychiatric diseases. Metabolism of arachidonic acid (AA) through the phospholipase A 2 (PLA 2 )/ prostaglandin-endoperoxide synthase (PTGS) pathway is increased after excitotoxic stimulation. However, the individual roles of the PTGS isoforms in this process are not well established. We assessed the role of the PTGS isoforms in the process of excitotoxicity by exposing mice deficient in either PTGS-1 (PTGS-1 -/-) or PTGS-2 (PTGS-2 -/-) to the rototypic excitotoxin, kainic acid (KA). Seizure intensity and neuronal damage were significantly elevated in KA-exposed PTGS-2 -/-, but not in PTGS-1 -/-, mice. The increased susceptibility was not associated with an alteration in KA receptor binding activity or mediated through the CB1 endocannabinoid receptor. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was decreased in the CA1 pyramidal neurons of PTGS-2 -/-mice, suggesting an alteration of GABAergic function. In wild-type mice, six weeks treatment with the PTGS-2 selective inhibitor celecoxib recapitulated the increased susceptibility to KA-induced excitotoxicity observed in PTGS-2 -/-mice, further supporting the role of PTGS-2 in the excitotoxic process. The increased susceptibility to KA was also associated with decreased brain levels of PGE 2 , a biomarker of PTGS-2 activity. Our results suggest that PTGS-2 activity and its specific products may modulate neuronal excitability by affecting GABAergic neurotransmission. Further, inhibition of PTGS-2 but not PTGS-1, may increase the susceptibility to seizures.

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“…In contrast, the depolarization, the increase in the power of γ oscillations, and the increased discharge found at a low and in the early phase of a high concentration of baclofen applications plausibly reflects an indirect action, whereby presynaptic GABA B Rs on axon terminals of interneurons reduce the release of GABA and result in a disinhibition of PCs. The disinhibitory effect is likely to involve extrasynaptic GABA A Rmediated tonic inhibition, known to be enhanced in principal cells in the epileptic hippocampus (31).…”

Section: Discussionmentioning

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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Multiple and Plastic Receptors Mediate Tonic GABA_AReceptor Currents in the Hippocampus

Cited by 211 publications

References 49 publications

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice

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

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Multiple and Plastic Receptors Mediate Tonic GABAAReceptor Currents in the Hippocampus

Cited by 211 publications

References 49 publications

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice

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

Contact Info

Product

Resources

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Multiple and Plastic Receptors Mediate Tonic GABA_AReceptor Currents in the Hippocampus

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