Subcellular Localization of Metabotropic GABABReceptor Subunits GABAB1a/band GABAB2in the Rat Hippocampus

Kulik, Ákos; Vida, Imre; Luján, Rafael; Haas, Carola A.; López‐Bendito, Guillermina; Shigemoto, Ryuichi; Frotscher, Michael

doi:10.1523/jneurosci.23-35-11026.2003

Cited by 217 publications

(264 citation statements)

References 78 publications

(124 reference statements)

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“…Enhanced γ frequency oscillations in epileptic patients are often observed at seizure onset in depth EEG recordings (5), suggesting that the high-frequency oscillations promote hypersynchronization and transition to pathological activity. During oscillations, due to the heightened synchronized activity of interneurons, GABA levels increase in the extracellular space and lead to activation of extrasynaptic GABA B Rs (10,47,48). Due to their higher affinity (34), first presynaptic receptors will be activated, leading to disinhibition in the epileptic network, which in a positive feedback manner will further enhance oscillations.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…GABA B Rs are expressed both postsynaptically in somatodendritic compartments and presynaptically in axon terminals, in excitatory principal cell and inhibitory interneurons (9)(10)(11). The effects of GABA B R activation on the network are dominated by inhibition leading to an overall dampened population activity.…”

mentioning

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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“…Electron microscopic studies showed that GABABR2 is more abundant on postsynaptic than presynaptic side with a dominant extrasynaptic membrane localization. Moreover, besides its main GABAergic synaptic localization it is also associated with putative glutamatergic synapses suggesting its involvement in both GABAergic and glutamatergic neurotransmission (Kulik et al, 2003).…”

Section: Chronic Cerebral Hypoperfusion Effects On Gabaergic / Glutammentioning

confidence: 99%

Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex

et al. 2017

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Chronic cerebral hypoperfusion (CCH) evokes mild cognitive impairment (MCI) and contributes to the progression of vascular dementia and Alzheimer's disease (AD). How CCH 2 induces these neurodegenerative processes that may spread along the synaptic network and whether they are detectable at the synaptic proteome level of the cerebral cortex remains to be established.In the present study, we report the synaptic protein changes in the cerebral cortex after stepwise bilateral common carotid artery occlusion (BCCAO) induced CCH in the rat. The occlusions were confirmed with Magnetic Resonance Angiography 5 weeks after the surgery.Synaptosome fractions were prepared using sucrose gradient centrifugation from cerebral cortex dissected 7 weeks after the occlusion. The synaptic protein differences between the sham operated and CCH groups were analysed with label free nanoUHPLC-MS/MS.

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“…GABA B receptors convey the metabotropic action of GABA, 2 the main inhibitory neurotransmitter in the brain (1). They are concentrated at axonal boutons of GABAergic and glutamatergic neurons as well as in dendritic spines and shafts at extrasynaptic sites (2).…”

mentioning

confidence: 99%

“…They are concentrated at axonal boutons of GABAergic and glutamatergic neurons as well as in dendritic spines and shafts at extrasynaptic sites (2). Presynaptic GABA B receptors primarily inhibit calcium channels regulating evoked neurotransmitter release, whereas postsynaptic GABA B receptors mainly open G-protein-regulated inwardly rectifying potassium channels and thereby elicit slow inhibitory postsynaptic potentials.…”

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confidence: 99%

GABAB Receptor Constituents Revealed by Tandem Affinity Purification from Transgenic Mice

Bartoi

Rigbolt

et al. 2010

Journal of Biological Chemistry

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GABA B receptors function as heterodimeric G-protein-coupled receptors for the neurotransmitter ␥-aminobutyric acid (GABA). Receptor subtypes, based on isoforms of the ligandbinding subunit GABA B1 , are thought to involve a differential set of associated proteins. Here, we describe two mouse lines that allow a straightforward biochemical isolation of GABA B receptors. The transgenic mice express GABA B1 isoforms that contain sequences for a two-step affinity purification, in addition to their endogenous subunit repertoire. Comparative analyses of purified samples from the transgenic mice and wild-type control animals revealed two novel components of the GABA B1 complex. One of the identified proteins, potassium channel tetramerization domain-containing protein 12, associates with heterodimeric GABA B receptors via the GABA B2 subunit. In transfected hippocampal neurons, potassium channel tetramerization domain-containing protein 12 augmented axonal surface targeting of GABA B2 . The mice equipped with tags on GABA B1 facilitate validation and identification of native binding partners of GABA B receptors, providing insight into the molecular mechanisms of synaptic modulation.GABA B receptors convey the metabotropic action of GABA, 2 the main inhibitory neurotransmitter in the brain (1). They are concentrated at axonal boutons of GABAergic and glutamatergic neurons as well as in dendritic spines and shafts at extrasynaptic sites (2). Presynaptic GABA B receptors primarily inhibit calcium channels regulating evoked neurotransmitter release, whereas postsynaptic GABA B receptors mainly open G-protein-regulated inwardly rectifying potassium channels and thereby elicit slow inhibitory postsynaptic potentials. Additionally, GABA B receptor activation decreases the local cAMP level. GABA B receptors function as heteromeric G-protein-coupled receptors consisting of two subunits, GABA B1 and GABA B2 . Heterodimerization is a prerequisite for both surface trafficking of the receptor and ligand-stimulated activation of a G i/o -protein (3).Two N-terminal GABA B1 variants, termed GABA B1a and GABA B1b differing only by a pair of sushi repeats that is exclusively present in GABA B1a , have been identified (4). They originate from the use of alternative transcriptional start sites (3, 5, 6) and underlie functional subtypes of the GABA B receptor with differential localization to pre-and postsynaptic sites in hippocampus and cortex (7-9). Because the sushi repeats are the only difference between GABA B1a and GABA B1b , it is to be expected that proteins interacting with these domains target or retain the GABA B1a isoform to specific microdomains. Consistently, a soluble recombinant protein of the two sushi repeats binds to neuronal membranes with low nanomolar affinity (10). An interaction of one of the two sushi repeats with fibulin-2 has been described (11), but the functional implication remains elusive.Further subtypes of the GABA B receptor may be formed by a compartment-specific interaction of additional proteins, e.g. e...

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Subcellular Localization of Metabotropic GABA_BReceptor Subunits GABA_B1a/band GABA_B2in the Rat Hippocampus

Cited by 217 publications

References 78 publications

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

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

Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex

GABAB Receptor Constituents Revealed by Tandem Affinity Purification from Transgenic Mice

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Subcellular Localization of Metabotropic GABABReceptor Subunits GABAB1a/band GABAB2in the Rat Hippocampus

Cited by 217 publications

References 78 publications

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

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

Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex

GABAB Receptor Constituents Revealed by Tandem Affinity Purification from Transgenic Mice

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Subcellular Localization of Metabotropic GABA_BReceptor Subunits GABA_B1a/band GABA_B2in the Rat Hippocampus

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

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